Drug Information

Drug (ID: DG00095) and It's Reported Resistant Information

Name	Tamoxifen
Synonyms	Tamoxifen; 10540-29-1; trans-Tamoxifen; Crisafeno; Soltamox; Tamoxifene; Diemon; Tamoxifenum; Tamoxifeno; Tamizam; Istubol; Tamoxen; Citofen; Oncomox; Valodex; Retaxim; Tamoxifene [INN-French]; Tamoxifenum [INN-Latin]; Tamoxifeno [INN-Spanish]; Tamoxifen (Z); Tamoxifen and its salts; Tamoxifen [INN:BAN]; ICI-46474; ICI 47699; TRANS FORM OF TAMOXIFEN; CCRIS 3275; UNII-094ZI81Y45; HSDB 6782; CHEMBL83; EINECS 234-118-0; 1-p-beta-Dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene; Citofen; Nourytam; Novaldex; Tamone; Tamoxifeno;Tamoxifenum; Tomaxithen; Gen-Tamoxifen; Istubal (TN); Nolvadex (TN); Nolvadex-D; Novo-Tamoxifen; Pms-Tamoxifen; Tamoplex (TN); Tamoxifen (INN); Tamoxifen (TN); Trans-Tamoxifen; Valodex (TN); TAMOXIFEN (TAMOXIFEN CITRATE (54965-24-1)); Trans-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine; (Z)-1-(p-Dimethylaminoethoxyphenyl)-1,2-diphenyl-1-butene; (Z)-2-(4-(1,2-Diphenyl-1-butenyl)phenoxy)-N,N-dimethylethanamine; (Z)-2-(4-(1,2-diphenylbut-1-enyl)phenoxy)-N,N-dimethylethanamine; (Z)-2-(para-(1,2-Diphenyl-1-butenyl)phenoxy)-N,N-dimethylamine (IUPAC); (Z)-2-[4-(1,2)-DIPHENYL-1-BUTENYL)-PHENOXY]-N,N-DIMETHYLETHANAMINE; (Z)-2-[p-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine; 1-p-beta-Dimethylamino-ethoxyphenyl-trans-1,2-diphenylbut-1-ene; 1-para-beta-Dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene; 2-[4-[(Z)-1,2-diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine; 2-{4-[(1Z)-1,2-diphenylbut-1-en-1-yl]phenoxy}-N,N-dimethylethanamine; Tamoxifen (Hormonal therapy); [3H]tamoxifen Click to Show/Hide
Indication	In total 1 Indication(s) Breast cancer [ICD-11: 2C60] Approved [1]
Structure
Drug Resistance Disease(s)	Disease(s) with Clinically Reported Resistance for This Drug (3 diseases) Breast cancer [ICD-11: 2C60] [2] Lung cancer [ICD-11: 2C25] [3] Ovarian cancer [ICD-11: 2C73] [3] Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases) Breast cancer [ICD-11: 2C60] [4]
Target	Estrogen receptor (ESR)	ESR1_HUMAN	[1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula	C26H29NO
IsoSMILES	CC/C(=C(\\C1=CC=CC=C1)/C2=CC=C(C=C2)OCCN(C)C)/C3=CC=CC=C3
InChI	1S/C26H29NO/c1-4-25(21-11-7-5-8-12-21)26(22-13-9-6-10-14-22)23-15-17-24(18-16-23)28-20-19-27(2)3/h5-18H,4,19-20H2,1-3H3/b26-25-
InChIKey	NKANXQFJJICGDU-QPLCGJKRSA-N
PubChem CID	2733526
ChEBI ID	CHEBI:41774
TTD Drug ID	D07KSG
VARIDT ID	DR00193
DrugBank ID	DB00675

Type(s) of Resistant Mechanism of This Drug

ADTT: Aberration of the Drug's Therapeutic Target

EADR: Epigenetic Alteration of DNA, RNA or Protein

MRAP: Metabolic Reprogramming via Altered Pathways

RTDM: Regulation by the Disease Microenvironment

UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Click to Show/Hide the Resistance Disease of This Class

Breast cancer [ICD-11: 2C60]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Forkhead box protein O3 (FOXO3)				[5]
Metabolic Type	Glucose metabolism
Sensitive Disease	Breast adenocarcinoma [ICD-11: 2C60.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Breast cancer [ICD-11: 2C60]
The Specified Disease	Breast adenocarcinoma
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.21E-11 Fold-change: 8.33E-01 Z-score: 7.07E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Adrenergic signaling in cardiomyocytes		Activation	hsa04261
In Vitro Model	ZR-75-1 cells	Breast	Homo sapiens (Human)	CVCL_0588
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Here, we report, for the first time, an additional mechanism through which an active FoxO3a can counteract Tam resistance in BCCs. Our data demonstrate how FoxO5a can affect multiple biochemical pathways of BC cell metabolism, spanning from the impairment of glucose breakdown, mitochondrial functionality and NADPH production to the induction of ROS production.
Key Molecule: Forkhead box protein O3 (FOXO3)				[5]
Metabolic Type	Glucose metabolism
Sensitive Disease	Breast adenocarcinoma [ICD-11: 2C60.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Breast cancer [ICD-11: 2C60]
The Specified Disease	Breast adenocarcinoma
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.21E-11 Fold-change: 8.33E-01 Z-score: 7.07E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Adrenergic signaling in cardiomyocytes		Activation	hsa04261
In Vitro Model	T-47D cells	N.A.	Homo sapiens (Human)	CVCL_0553
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Here, we report, for the first time, an additional mechanism through which an active FoxO3a can counteract Tam resistance in BCCs. Our data demonstrate how FoxO4a can affect multiple biochemical pathways of BC cell metabolism, spanning from the impairment of glucose breakdown, mitochondrial functionality and NADPH production to the induction of ROS production.
Key Molecule: Forkhead box protein O3 (FOXO3)				[5]
Metabolic Type	Glucose metabolism
Sensitive Disease	Breast adenocarcinoma [ICD-11: 2C60.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Breast cancer [ICD-11: 2C60]
The Specified Disease	Breast adenocarcinoma
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.21E-11 Fold-change: 8.33E-01 Z-score: 7.07E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Adrenergic signaling in cardiomyocytes		Activation	hsa04261
In Vitro Model	MCF7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Here, we report, for the first time, an additional mechanism through which an active FoxO3a can counteract Tam resistance in BCCs. Our data demonstrate how FoxO3a can affect multiple biochemical pathways of BC cell metabolism, spanning from the impairment of glucose breakdown, mitochondrial functionality and NADPH production to the induction of ROS production.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Metalloproteinase inhibitor 3 (TIMP3)				[8]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Breast cancer [ICD-11: 2C60]
The Specified Disease	Breast cancer
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.70E-17 Fold-change: 1.51E+00 Z-score: 9.28E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	WST-8 assay
Mechanism Description	Transfection of AS-miR-221 and AS-miR-222 dramatically inhibited expression of miR-221 and miR-222, respectively, in both MCF-7 and MDA-MB-231 cells (P<0.05-0.01). Down-regulation of miR-221/222 significantly increased the expression of TIMP3 compared with controls (P<0.05-0.01). The viability of estrogen receptor (ER)-positive MCF-7 cells transfected with AS-miR-221 or/and AS-miR-222 was significantly reduced by tamoxifen (P<0.05-0.01). Suppression of miRNA-221/222 increases the sensitivity of ER-positive MCF-7 breast cancer cells to tamoxifen. This effect is mediated through upregulation of TIMP3. These findings suggest that upregulation of TIMP3 via inhibition of miRNA-221/222 could be a promising therapeutic approach for breast cancer.
Key Molecule: Estrogen receptor alpha (ESR1)				[11]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Breast cancer [ICD-11: 2C60]
The Specified Disease	Breast cancer
The Studied Tissue	Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.93E-18 Fold-change: 9.62E-02 Z-score: 8.85E+00
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	SkBR3 cells	Breast	Homo sapiens (Human)	CVCL_0033
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	BT474 cells	Breast	Homo sapiens (Human)	CVCL_0179
	MDA-MB-453 cells	Breast	Homo sapiens (Human)	CVCL_0418
	MDA-MB-468 cells	Breast	Homo sapiens (Human)	CVCL_0419
	Hs-578T cells	Breast	Homo sapiens (Human)	CVCL_0332
	MCF10A cells	Breast	Homo sapiens (Human)	CVCL_0598
	MDA-MB-157 cells	Breast	Homo sapiens (Human)	CVCL_0618
	MDA-MB-361 cells	Breast	Homo sapiens (Human)	CVCL_0620
	MDA-MB-435s cells	Breast	Homo sapiens (Human)	CVCL_0622
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-221 and miR-222 are frequently up-regulated in ERalpha-negative breast cancer cell lines and primary tumors. The elevated level of miR-221 and miR-222 is responsible for a subset of ERalpha-negative breast tumors that express ERalpha mRNA. Furthermore, overexpression of miR-221 and miR-222 contributes to tamoxifen resistance through negative regulation of ERalpha, whereas knockdown of miR-221 and/or miR-222 restores ERalpha expression and tamoxifen sensitivity.
Key Molecule: Homeobox protein Hox-B3 (HOXB3)				[20]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Breast cancer [ICD-11: 2C60]
The Specified Disease	Breast cancer
The Studied Tissue	Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.06E-04 Fold-change: -2.51E-02 Z-score: -3.73E+00
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR375 inhibits cancer stem cell phenotype and tamoxifen resistance by degrading HOXB3 in human ER-positive breast cancer Overexpression of HOXB3 induced formation of CSC phenotypes, EMT and tamoxifen-resistance as well as enhanced ability of migration and invasion in MCF-7 cells.
Key Molecule: B-cell lymphoma/leukemia 11A (BCL11A)				[21]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Breast cancer [ICD-11: 2C60]
The Specified Disease	Breast cancer
The Studied Tissue	Breast tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.20E-14 Fold-change: -1.12E-01 Z-score: -7.79E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Inhibition	hsa04010
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vitro Model	MCF-7R cells	Breast	Homo sapiens (Human)	CVCL_Y493
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RIP assay; Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Shikonin reduces tamoxifen resistance of MCF-7R breast cancer cells by inducing uc.57, which downregulates BCL11A to inhibit PI3k/AkT and MAPk signaling pathways.
Key Molecule: Phosphatase and tensin homolog (PTEN)				[31]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	Western blot analysis; RT-qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	Low expression of ADAMTS9-AS2 inhibits PTEN expression and enhances tamoxifen resistance through targeting microRNA-130a-5p.
Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2)				[51]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	MCF7/TAMR cells	Breast	Homo sapiens (Human)	CVCL_EG55
	T47D/TAMR cells	Breast	Homo sapiens (Human)	CVCL_1D36
Experiment for Molecule Alteration	Western blot analysis; Luciferase reporter assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	The ERBB2 expression is regulated at the post-transcriptional level by miR26a/b and the RNA-binding protein human antigen R, miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA.
Key Molecule: Eukaryotic translation initiation factor 4 gamma 1 (EIF4G1)				[53]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vitro Model	MCF-7/ADR cells	Breast	Homo sapiens (Human)	CVCL_1452
Experiment for Molecule Alteration	Western blot analysis; Luciferase reporter assay
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis
Mechanism Description	Down-regulation of eIF4G by microRNA-503 enhances drug sensitivity of MCF-7/ADR cells through suppressing the expression of ABC transport proteins.
Key Molecule: CD166 antigen (ALCAM)				[54]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	Western blot analysis; Dual luciferase assay
Experiment for Drug Resistance	CCK8 assay; Annexin V-FITC Apoptosis Detection assay; Flow cytometry assay
Mechanism Description	miR148a and miR152 reduce tamoxifen resistance in ER+ breast cancer via downregulating ALCAM.
Key Molecule: Estrogen receptor alpha (ESR1)				[55]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vitro Model	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	ATP-content assay
Mechanism Description	miR-27a sensitizes luminal A breast cancer cells to SERM treatments based on a positive feedback loop with ERalpha.
Key Molecule: Protein zeta/delta 14-3-3 (YWHAZ)				[56]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	AKT/mTOR signaling pathway		Regulation	N.A.
	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vitro Model	LCC2 cells	Breast	Homo sapiens (Human)	CVCL_DP51
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Over-expression of miR-451a can enhance MCF-7 and LCC2 cell sensitivity to TAM. Opposite effects were elicited by knocking down miR-451a. TAM treatment can up-regulate 14-3-3Zeta expression, and down-regulate ERalpha expression. 14-3-3Zeta and ERalpha were shown to interact. Over-expression of miR-451a decreased 14-3-3Zeta expression and increased ERalpha expression, suppressing cell proliferation, increasing apoptosis, and reducing activation of p-AkT and p-mTOR.
Key Molecule: Estrogen receptor alpha (ESR1)				[56]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	AKT/mTOR signaling pathway		Regulation	N.A.
	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vitro Model	LCC2 cells	Breast	Homo sapiens (Human)	CVCL_DP51
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Over-expression of miR-451a can enhance MCF-7 and LCC2 cell sensitivity to TAM. Opposite effects were elicited by knocking down miR-451a. TAM treatment can up-regulate 14-3-3Zeta expression, and down-regulate ERalpha expression. 14-3-3Zeta and ERalpha were shown to interact. Over-expression of miR-451a decreased 14-3-3Zeta expression and increased ERalpha expression, suppressing cell proliferation, increasing apoptosis, and reducing activation of p-AkT and p-mTOR.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[57]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT/mTOR signaling pathway		Regulation	N.A.
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 is a miRNA that is overexpressed in most tumor types, and acts as an oncogene by targeting many suppressor genes related to proliferation, apoptosis, and invasion. miR-21 facilitates tumor growth and invasion by targeting programmed cell death 4 (PDCD4), PTEN, and Bcl-2. silencing of miR-21 sensitized ER+ breast cancer cells to TAM and FUL induced cell apoptosis.
Key Molecule: Programmed cell death protein 4 (PDCD4)				[57]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT/mTOR signaling pathway		Regulation	N.A.
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 is a miRNA that is overexpressed in most tumor types, and acts as an oncogene by targeting many suppressor genes related to proliferation, apoptosis, and invasion. miR-21 facilitates tumor growth and invasion by targeting programmed cell death 4 (PDCD4), PTEN, and Bcl-2. silencing of miR-21 sensitized ER+ breast cancer cells to TAM and FUL induced cell apoptosis.
Key Molecule: Phosphatase and tensin homolog (PTEN)				[57]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT/mTOR signaling pathway		Regulation	N.A.
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 is a miRNA that is overexpressed in most tumor types, and acts as an oncogene by targeting many suppressor genes related to proliferation, apoptosis, and invasion. miR-21 facilitates tumor growth and invasion by targeting programmed cell death 4 (PDCD4), PTEN, and Bcl-2. silencing of miR-21 sensitized ER+ breast cancer cells to TAM and FUL induced cell apoptosis.
Key Molecule: Mitochondrial uncoupling protein 2 (UCP2)				[58]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT/mTOR signaling pathway		Activation	hsa04151
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	TAM and FUL treatment induced apoptosis as well as autophagy in the ER+ breast cancer cells. Autophagy is a major cause of resistance to TAM and FUL. miR-214 increased the sensitivity of breast cancers to TAM and FUL through inhibition of autophagy by targeting UCP2.
Key Molecule: Clathrin heavy chain 1 (CLTC)				[59]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	293T cells	Breast	Homo sapiens (Human)	CVCL_0063
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTS or WST-8 assay
Mechanism Description	Loss and gain of miR-574-3p function in MCF-7 cells causes CLTC to be upregulated and downregulated, respectively. And CLTC siRNA knockdown restores tamoxifen sensitivity, and low CLTC levels are correlated with better survival in tamoxifen-treated breast cancer patients.
Key Molecule: Estrogen receptor alpha (ESR1)				[39]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ER-alpha 36 mediated nongenomic estrogen signaling pathway		Inhibition	hsa04915
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	SkBR3 cells	Breast	Homo sapiens (Human)	CVCL_0033
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	ZR75-1 cells	Breast	Homo sapiens (Human)	CVCL_0588
	MDA-MB-436 cells	Breast	Homo sapiens (Human)	CVCL_0623
	MDA-MB-468 cells	Breast	Homo sapiens (Human)	CVCL_0419
	184A1 cells	Breast	Homo sapiens (Human)	CVCL_3040
	HB3396 cells	Breast	Homo sapiens (Human)	N.A.
	MEGM cells	Breast	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	Luciferase assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	Let-7 miRNAs (b and i) enhanced tamoxifen sensitivity of tamoxifen-resistant breast cancer cells by targeting ER-alpha36 expression.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Cadherin-1 (CDH1)				[10]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Breast cancer [ICD-11: 2C60]
The Specified Disease	Breast cancer
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 7.17E-05 Fold-change: 1.76E-01 Z-score: 4.06E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell viability		Inhibition	hsa05200
	Wnt signaling pathway		Inhibition	hsa04310
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vitro Model	SkBR3 cells	Breast	Homo sapiens (Human)	CVCL_0033
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	Knockdown of H19 by siRNA transfection can significantly reduce the expression of N-cadherin, as well as increase E-cadherin and vimentin level, which improved tamoxifen sensitivity in tamoxifen-resistant breast cancer cells.
Key Molecule: hsa-mir-205				[46]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	MCF10A cells	Breast	Homo sapiens (Human)	CVCL_0598
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	In MDA-MB-231 cells, down-regulated LncRNA-ROR could inhibit the EMT of breast cancer cells and enhance the sensibility of breast cancer cells to tamoxifen by increasing miR205 expression and suppressing the expressions of ZEB1 and ZEB2.
Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1)				[46]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	MCF10A cells	Breast	Homo sapiens (Human)	CVCL_0598
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	In MDA-MB-231 cells, down-regulated LncRNA-ROR could inhibit the EMT of breast cancer cells and enhance the sensibility of breast cancer cells to tamoxifen by increasing miR205 expression and suppressing the expressions of ZEB1 and ZEB2.
Key Molecule: Long non-protein coding RNA, regulator of reprogramming (LINC-ROR)				[46]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	MCF10A cells	Breast	Homo sapiens (Human)	CVCL_0598
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	In MDA-MB-231 cells, down-regulated LncRNA-ROR could inhibit the EMT of breast cancer cells and enhance the sensibility of breast cancer cells to tamoxifen by increasing miR205 expression and suppressing the expressions of ZEB1 and ZEB2.
Key Molecule: Zinc finger E-box-binding homeobox 2 (ZEB2)				[46]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	MCF10A cells	Breast	Homo sapiens (Human)	CVCL_0598
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The miR205-5p and miR200 families can silence ZEB1 and ZEB2 expression. LncRNA-ROR functions as a molecular sponge for miR205-5p and affects the target genes ZEB1 and ZEB2, which in turn influences the EMT process in breast cancer cells.
Key Molecule: H19, imprinted maternally expressed transcript (H19)				[10]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell viability		Inhibition	hsa05200
	Wnt signaling pathway		Inhibition	hsa04310
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vitro Model	SkBR3 cells	Breast	Homo sapiens (Human)	CVCL_0033
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	Knockdown of H19 by siRNA transfection can significantly reduce the expression of N-cadherin, as well as increase E-cadherin and vimentin level, which improved tamoxifen sensitivity in tamoxifen-resistant breast cancer cells.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-130a-5p				[31]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	Low expression of ADAMTS9-AS2 inhibits PTEN expression and enhances tamoxifen resistance through targeting microRNA-130a-5p.
Key Molecule: H19, imprinted maternally expressed transcript (H19)				[50]
Sensitive Disease	ER positive breast cancer [ICD-11: 2C60.6]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	LCC2 cells	Breast	Homo sapiens (Human)	CVCL_DP51
	LCC9 cells	Breast	Homo sapiens (Human)	CVCL_DP52
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	WST-8 assay
Mechanism Description	H19 plays a central role in maintaining endocrine therapy resistance by modulating ERalpha expression in these cells. Moreover, decreasing H19 levels using pharmacological inhibitors, that inhibit pathways regulating H19 expression in the ETR cells, helps overcome Tamoxifen and Fulvestrant-resistance.
Key Molecule: Long non-protein coding RNA (uc.57)				[21]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Inhibition	hsa04010
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vitro Model	MCF-7R cells	Breast	Homo sapiens (Human)	CVCL_Y493
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Shikonin reduces tamoxifen resistance of MCF-7R breast cancer cells by inducing uc.57, which downregulates BCL11A to inhibit PI3k/AkT and MAPk signaling pathways.
Key Molecule: hsa-mir-26a				[51]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	MCF7/TAMR cells	Breast	Homo sapiens (Human)	CVCL_EG55
	T47D/TAMR cells	Breast	Homo sapiens (Human)	CVCL_1D36
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	The ERBB2 expression is regulated at the post-transcriptional level by miR26a/b and the RNA-binding protein human antigen R, miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA.
Key Molecule: hsa-mir-26b				[51]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	MCF7/TAMR cells	Breast	Homo sapiens (Human)	CVCL_EG55
	T47D/TAMR cells	Breast	Homo sapiens (Human)	CVCL_1D36
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	The ERBB2 expression is regulated at the post-transcriptional level by miR26a/b and the RNA-binding protein human antigen R, miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA.
Key Molecule: Long non-protein coding RNA, regulator of reprogramming (LINC-ROR)				[52]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell autophagy		Inhibition	hsa04140
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	BT474 cells	Breast	Homo sapiens (Human)	CVCL_0179
	MCF10A cells	Breast	Homo sapiens (Human)	CVCL_0598
	MDA-MB-435 cells	Breast	Homo sapiens (Human)	CVCL_0417
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Transwell assay
Mechanism Description	Inhibition of long non-coding RNA ROR reverses resistance to Tamoxifen by inducing autophagy in breast cancer Downregulated long non-coding RNA ROR suppressed BT474 cell proliferation, invasion, and migration.
Key Molecule: hsa-mir-503				[53]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vitro Model	MCF-7/ADR cells	Breast	Homo sapiens (Human)	CVCL_1452
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis
Mechanism Description	Down-regulation of eIF4G by microRNA-503 enhances drug sensitivity of MCF-7/ADR cells through suppressing the expression of ABC transport proteins.
Key Molecule: hsa-mir-375				[20]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR375 inhibits cancer stem cell phenotype and tamoxifen resistance by degrading HOXB3 in human ER-positive breast cancer Overexpression of HOXB3 induced formation of CSC phenotypes, EMT and tamoxifen-resistance as well as enhanced ability of migration and invasion in MCF-7 cells.
Key Molecule: hsa-mir-148a				[54]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Annexin V-FITC Apoptosis Detection assay; Flow cytometry assay
Mechanism Description	miR148a and miR152 reduce tamoxifen resistance in ER+ breast cancer via downregulating ALCAM.
Key Molecule: hsa-mir-152				[54]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Annexin V-FITC Apoptosis Detection assay; Flow cytometry assay
Mechanism Description	miR148a and miR152 reduce tamoxifen resistance in ER+ breast cancer via downregulating ALCAM.
Key Molecule: hsa-mir-27a				[55]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vitro Model	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	ATP-content assay
Mechanism Description	miR-27a sensitizes luminal A breast cancer cells to SERM treatments based on a positive feedback loop with ERalpha.
Key Molecule: hsa-miR-451a				[56]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	AKT/mTOR signaling pathway		Regulation	N.A.
	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vitro Model	LCC2 cells	Breast	Homo sapiens (Human)	CVCL_DP51
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	Over-expression of miR-451a can enhance MCF-7 and LCC2 cell sensitivity to TAM. Opposite effects were elicited by knocking down miR-451a. TAM treatment can up-regulate 14-3-3Zeta expression, and down-regulate ERalpha expression. 14-3-3Zeta and ERalpha were shown to interact. Over-expression of miR-451a decreased 14-3-3Zeta expression and increased ERalpha expression, suppressing cell proliferation, increasing apoptosis, and reducing activation of p-AkT and p-mTOR.
Key Molecule: hsa-mir-21				[57]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT/mTOR signaling pathway		Regulation	N.A.
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 is a miRNA that is overexpressed in most tumor types, and acts as an oncogene by targeting many suppressor genes related to proliferation, apoptosis, and invasion. miR-21 facilitates tumor growth and invasion by targeting programmed cell death 4 (PDCD4), PTEN, and Bcl-2. silencing of miR-21 sensitized ER+ breast cancer cells to TAM and FUL induced cell apoptosis.
Key Molecule: hsa-mir-214				[58]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT/mTOR signaling pathway		Activation	hsa04151
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	TAM and FUL treatment induced apoptosis as well as autophagy in the ER+ breast cancer cells. Autophagy is a major cause of resistance to TAM and FUL. miR-214 increased the sensitivity of breast cancers to TAM and FUL through inhibition of autophagy by targeting UCP2.
Key Molecule: hsa-miR-574-3p				[59]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	293T cells	Breast	Homo sapiens (Human)	CVCL_0063
Experiment for Molecule Alteration	qPCR; qRT-PCR
Experiment for Drug Resistance	MTS or WST-8 assay
Mechanism Description	Loss and gain of miR-574-3p function in MCF-7 cells causes CLTC to be upregulated and downregulated, respectively. And CLTC siRNA knockdown restores tamoxifen sensitivity, and low CLTC levels are correlated with better survival in tamoxifen-treated breast cancer patients.
Key Molecule: hsa-mir-221				[8]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	WST-8 assay
Mechanism Description	Transfection of AS-miR-221 and AS-miR-222 dramatically inhibited expression of miR-221 and miR-222, respectively, in both MCF-7 and MDA-MB-231 cells (P<0.05-0.01). Down-regulation of miR-221/222 significantly increased the expression of TIMP3 compared with controls (P<0.05-0.01). The viability of estrogen receptor (ER)-positive MCF-7 cells transfected with AS-miR-221 or/and AS-miR-222 was significantly reduced by tamoxifen (P<0.05-0.01). Suppression of miRNA-221/222 increases the sensitivity of ER-positive MCF-7 breast cancer cells to tamoxifen. This effect is mediated through upregulation of TIMP3. These findings suggest that upregulation of TIMP3 via inhibition of miRNA-221/222 could be a promising therapeutic approach for breast cancer.
Key Molecule: hsa-mir-222				[8]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	WST-8 assay
Mechanism Description	Transfection of AS-miR-221 and AS-miR-222 dramatically inhibited expression of miR-221 and miR-222, respectively, in both MCF-7 and MDA-MB-231 cells (P<0.05-0.01). Down-regulation of miR-221/222 significantly increased the expression of TIMP3 compared with controls (P<0.05-0.01). The viability of estrogen receptor (ER)-positive MCF-7 cells transfected with AS-miR-221 or/and AS-miR-222 was significantly reduced by tamoxifen (P<0.05-0.01). Suppression of miRNA-221/222 increases the sensitivity of ER-positive MCF-7 breast cancer cells to tamoxifen. This effect is mediated through upregulation of TIMP3. These findings suggest that upregulation of TIMP3 via inhibition of miRNA-221/222 could be a promising therapeutic approach for breast cancer.
Key Molecule: hsa-let-7b				[39]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ER-alpha 36 mediated nongenomic estrogen signaling pathway		Inhibition	hsa04915
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	SkBR3 cells	Breast	Homo sapiens (Human)	CVCL_0033
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	ZR75-1 cells	Breast	Homo sapiens (Human)	CVCL_0588
	MDA-MB-436 cells	Breast	Homo sapiens (Human)	CVCL_0623
	MDA-MB-468 cells	Breast	Homo sapiens (Human)	CVCL_0419
	184A1 cells	Breast	Homo sapiens (Human)	CVCL_3040
	HB3396 cells	Breast	Homo sapiens (Human)	N.A.
	MEGM cells	Breast	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	Let-7 miRNAs (b and i) enhanced tamoxifen sensitivity of tamoxifen-resistant breast cancer cells by targeting ER-alpha36 expression.
Key Molecule: hsa-let-7i				[39]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	ER-alpha 36 mediated nongenomic estrogen signaling pathway		Inhibition	hsa04915
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	SkBR3 cells	Breast	Homo sapiens (Human)	CVCL_0033
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	ZR75-1 cells	Breast	Homo sapiens (Human)	CVCL_0588
	MDA-MB-436 cells	Breast	Homo sapiens (Human)	CVCL_0623
	MDA-MB-468 cells	Breast	Homo sapiens (Human)	CVCL_0419
	184A1 cells	Breast	Homo sapiens (Human)	CVCL_3040
	HB3396 cells	Breast	Homo sapiens (Human)	N.A.
	MEGM cells	Breast	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	Let-7 miRNAs (b and i) enhanced tamoxifen sensitivity of tamoxifen-resistant breast cancer cells by targeting ER-alpha36 expression.
Key Molecule: hsa-mir-221				[11]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	SkBR3 cells	Breast	Homo sapiens (Human)	CVCL_0033
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	BT474 cells	Breast	Homo sapiens (Human)	CVCL_0179
	MDA-MB-453 cells	Breast	Homo sapiens (Human)	CVCL_0418
	MDA-MB-468 cells	Breast	Homo sapiens (Human)	CVCL_0419
	Hs-578T cells	Breast	Homo sapiens (Human)	CVCL_0332
	MCF10A cells	Breast	Homo sapiens (Human)	CVCL_0598
	MDA-MB-157 cells	Breast	Homo sapiens (Human)	CVCL_0618
	MDA-MB-361 cells	Breast	Homo sapiens (Human)	CVCL_0620
	MDA-MB-435s cells	Breast	Homo sapiens (Human)	CVCL_0622
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-221 and miR-222 are frequently up-regulated in ERalpha-negative breast cancer cell lines and primary tumors. The elevated level of miR-221 and miR-222 is responsible for a subset of ERalpha-negative breast tumors that express ERalpha mRNA. Furthermore, overexpression of miR-221 and miR-222 contributes to tamoxifen resistance through negative regulation of ERalpha, whereas knockdown of miR-221 and/or miR-222 restores ERalpha expression and tamoxifen sensitivity.
Key Molecule: hsa-mir-222				[11]
Sensitive Disease	Breast cancer [ICD-11: 2C60.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	MCF-7 cells	Breast	Homo sapiens (Human)	CVCL_0031
	SkBR3 cells	Breast	Homo sapiens (Human)	CVCL_0033
	MDA-MB-231 cells	Breast	Homo sapiens (Human)	CVCL_0062
	T47D cells	Breast	Homo sapiens (Human)	CVCL_0553
	BT474 cells	Breast	Homo sapiens (Human)	CVCL_0179
	MDA-MB-453 cells	Breast	Homo sapiens (Human)	CVCL_0418
	MDA-MB-468 cells	Breast	Homo sapiens (Human)	CVCL_0419
	Hs-578T cells	Breast	Homo sapiens (Human)	CVCL_0332
	MCF10A cells	Breast	Homo sapiens (Human)	CVCL_0598
	MDA-MB-157 cells	Breast	Homo sapiens (Human)	CVCL_0618
	MDA-MB-361 cells	Breast	Homo sapiens (Human)	CVCL_0620
	MDA-MB-435s cells	Breast	Homo sapiens (Human)	CVCL_0622
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-221 and miR-222 are frequently up-regulated in ERalpha-negative breast cancer cell lines and primary tumors. The elevated level of miR-221 and miR-222 is responsible for a subset of ERalpha-negative breast tumors that express ERalpha mRNA. Furthermore, overexpression of miR-221 and miR-222 contributes to tamoxifen resistance through negative regulation of ERalpha, whereas knockdown of miR-221 and/or miR-222 restores ERalpha expression and tamoxifen sensitivity.

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Click to Show/Hide

Key Molecule: TP53-induced glycolysis and apoptosis regulator (TIGAR)

[6]

Metabolic Type

Glucose metabolism

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast adenocarcinoma

The Studied Tissue

Blood

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 5.20E-05

Fold-change: 2.53E-01

Z-score: 4.13E+00

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

Apoptosis rate assay

Mechanism Description

Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival

Key Molecule: Solute carrier family 16 member 1 (SLC16A1)

[7]

Metabolic Type

Glucose metabolism

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast adenocarcinoma

The Studied Tissue

Blood

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 7.57E-07

Fold-change: 3.14E-01

Z-score: 5.09E+00

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF7 cells

Breast

Homo sapiens (Human)

CVCL_0031

MDA-MB-231cells

Breast

Homo sapiens (Human)

CVCL_0062

SK-BR-3 cells

Pleural effusion

Homo sapiens (Human)

CVCL_0033

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

Cell viability assay

Mechanism Description

We identified monocarboxylate transporter1 (MCT1) and lactate dehydrogenase B (LDHB) as important mediators of lactate influx and its conversion to pyruvate, respectively. Consistently, AR-C155858 (MCT1 inhibitor) inhibited the proliferation, migration, spheroid formation, and in vivo tumor growth of TAMR-MCF-7 cells.

Key Molecule: Sodium/glucose cotransporter 1 (SGLT1)

[43]

Metabolic Type

Glucose metabolism

Resistant Disease

Estrogen receptor (ER)-positive breast cancer [ICD-11: 2C60.6]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

Estrogen receptor (ER)-positive breast cancer patient

Homo Sapiens

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

Cell prognosis assay

Mechanism Description

Here, we characterized sodium/glucose cotransporter 1 (SGLT1) overexpression drives the highly glycolytic phenotype of tamoxifen-resistant breast cancer cells where enhanced lactic acid secretion promotes M2-like TAM polarization via the hypoxia-inducible factor-1alpha/signal transducer and activator of transcription-4 pathway

Key Molecule: Fatty acid synthase (FASN)

[44]

Metabolic Type

Lipid metabolism

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

HCC patients

Homo Sapiens

Experiment for
Molecule Alteration

Western blot analysis

Mechanism Description

Our results revealed that FASN predominates under sensitive conditions, crucially contributing to aerobic respiration. However, its activity diminishes in advanced stages and in tamoxifen-resistant conditions. Conversely, the progressive upregulation of LDHA and the prevalence of anaerobic respiration emerged as metabolic signatures associated with the acquisition of tamoxifen resistance. Subsequently, we delineated the functional roles and metabolic adaptability in response to the inhibition of FASN and LDHA using cellular models representative of tamoxifen-resistant BC.

Key Molecule: Lactate dehydrogenase A (LDHA)

[44]

Metabolic Type

Lipid metabolism

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

HCC patients

Homo Sapiens

Experiment for
Molecule Alteration

Western blot analysis

Mechanism Description

Key Molecule: Lactate dehydrogenase B (LDHB)

[7]

Metabolic Type

Glucose metabolism

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF7 cells

Breast

Homo sapiens (Human)

CVCL_0031

MDA-MB-231cells

Breast

Homo sapiens (Human)

CVCL_0062

SK-BR-3 cells

Pleural effusion

Homo sapiens (Human)

CVCL_0033

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

Cell viability assay

Mechanism Description

Key Molecule: Fatty acid synthase (FASN)

[44]

Metabolic Type

Lipid metabolism

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF-10A cells

Breast

Homo sapiens (Human)

CVCL_0598

MCF-7 TamR cells

Breast

Homo sapiens (Human)

CVCL_0031

MCF7 cells

Breast

Homo sapiens (Human)

CVCL_0031

MDA-MB-231cells

Breast

Homo sapiens (Human)

CVCL_0062

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

Cell viability assay

Mechanism Description

Key Molecule: Lactate dehydrogenase A (LDHA)

[44]

Metabolic Type

Lipid metabolism

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF-10A cells

Breast

Homo sapiens (Human)

CVCL_0598

MCF-7 TamR cells

Breast

Homo sapiens (Human)

CVCL_0031

MCF7 cells

Breast

Homo sapiens (Human)

CVCL_0031

MDA-MB-231cells

Breast

Homo sapiens (Human)

CVCL_0062

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

Cell viability assay

Mechanism Description

Key Molecule: Ceramide kinase (CERK)

[45]

Metabolic Type

Lipid metabolism

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

293 T cells

Blood

Homo sapiens (Human)

N.A.

H3396 cells

Breast

Mus musculus (Mouse)

CVCL_D348

MCF7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

qRT-PCR; Western blot analysis

Experiment for
Drug Resistance

Apoptosis rate assay

Mechanism Description

Mechanistically, the elevated EHF expression transcriptionally up-regulates CERK expression to prohibit tamoxifen-induced sphingolipid ceramide accumulation, which then inhibits tamoxifen-mediated repression on PI3K/AKT dependent cell proliferation and its driven p53/caspase-3 mediated apoptosis in TAMR cells. This work provides insight into the regulation of sphingolipid metabolism in tamoxifen resistance and identifies a potential therapeutic target for this disease.

Key Molecule: Histone H3

[6]

Metabolic Type

Glucose metabolism

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Methylation

H3K36me2

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

Apoptosis rate assay

Mechanism Description

Key Molecule: Nuclear receptor binding SET domain protein 2 (NSD2)

[6]

Metabolic Type

Glucose metabolism

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

Apoptosis rate assay

Mechanism Description

Key Molecule: Sodium/glucose cotransporter 1 (SGLT1)

[43]

Metabolic Type

Glucose metabolism

Resistant Disease

Estrogen receptor (ER)-positive breast cancer [ICD-11: 2C60.6]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

Key Molecule: Sodium/glucose cotransporter 1 (SGLT1)

[43]

Metabolic Type

Glucose metabolism

Resistant Disease

Estrogen receptor (ER)-positive breast cancer [ICD-11: 2C60.6]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

T-47D cells

N.A.

Homo sapiens (Human)

CVCL_0553

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

Unusual Activation of Pro-survival Pathway (UAPP)

Click to Show/Hide

Key Molecule: Metalloproteinase-disintegrin ADAM22-3 (ADAM22)

[9]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Blood

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 3.97E-01

Fold-change: 3.50E-02

Z-score: 8.49E-01

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Cell viability

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

Decreased miR-449a causes the upregulation of ADAM22, which induces tamoxifen resistance of breast cancer cells.

Key Molecule: Ribonucleoside-diphosphate reductase subunit M2 (RRM2)

[12]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 3.61E-249

Fold-change: 6.99E-01

Z-score: 5.85E+01

Experimental Note

Revealed Based on the Cell Line Data

Mechanism Description

Increased expression of ribonucleotide reductase subunit M2 (RRM2) was found to be significantly linked to poor survival in all breast cancer patients as well as in ER-positive patients resistant to TAM. Azacytidine treatment in the TAMR cell line results in reduced proliferation and consequently resensitizes cells to TAM treatment. RRM2 is one of the isoforms of the enzyme ribonucleotide reductase, which is involved in the conversion of deoxyribonucleotides from their corresponding ribonucleotides that are required for DNA synthesis. A DNA methyl transferase inhibitor azacytidine has been shown to inhibit the expression of RRM2. Down-regulation of RRM2 by siRNA-mediated approaches significantly reduces TAMR cell growth, invasion and motility. RRM2 inhibition also leads to decreased expression of DNA repair enzymes and elevated expression of pro-apoptotic proteins such as BIM and BAX leading to apoptosis.

Key Molecule: Alpha-enolase (ENO1)

[12]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 3.20E-06

Fold-change: 6.37E-02

Z-score: 4.72E+00

Experimental Note

Revealed Based on the Cell Line Data

Mechanism Description

Hk2, PFkB3, ENO-1, and PkM-2 are the main enzymes of glycolysis and their expression is upregulated in TAMR cells. Hk2 is also involved in the activation of pro-survival autophagy. ENO-1 plays an important role by inhibiting apoptosis via downregulation of c-Myc. In mitochondria, PDk4 phosphorylation regulate Pyruvate dehydrogenase of PDC. NSD2 activates Hk-2, G6PD, and TIGAR expression and upregulates the PPP pathway. PPP produces NADH and Ribulose 5-Phosphate, a substrate for nucleotide biosynthesis. NADH reduces ROS and inhibits apoptosis. LDHA overexpression helps in aerobic glycolysis and indirectly promotes autophagy. To reduce the concentration of lactate in the cells, MCT expression is increased, which facilitates the efflux of lactate and cell survival.

Key Molecule: Hypoxia-inducible factor 1-alpha (HIF1A)

[13]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 2.47E-15

Fold-change: 4.39E-02

Z-score: 8.20E+00

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

BT474 cells

Breast

Homo sapiens (Human)

CVCL_0179

LCC2 cells

Breast

Homo sapiens (Human)

CVCL_DP51

LCC9 cells

Breast

Homo sapiens (Human)

CVCL_DP52

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

CCK8 assay; Soft agar colony formation assay; Flow cytometry assay

Mechanism Description

Long non-coding RNA UCA1 enhances tamoxifen resistance in breast cancer cells through a miR18a-HIF1alpha feedback regulatory loop. The upregulated UCA1 sponges miR18a, which is a negative regulator of HIF1alpha.

Key Molecule: Transcription factor E2F7 (E2F7)

[15]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 2.07E-215

Fold-change: 2.45E-01

Z-score: 3.81E+01

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell viability

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

SkBR3 cells

Breast

Homo sapiens (Human)

CVCL_0033

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

BT474 cells

Breast

Homo sapiens (Human)

CVCL_0179

Hs-578T cells

Breast

Homo sapiens (Human)

CVCL_0332

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Both miR-26a knockdown and E2F7 overexpression conferred resistance to TAM in MCF-7 cells and there is an inverse correlation between miR-26a and E2F7 expression.

Key Molecule: Mucin-1 (MUC1)

[12]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 1.85E-53

Fold-change: 2.32E-01

Z-score: 1.73E+01

Experimental Note

Revealed Based on the Cell Line Data

Mechanism Description

MUC1, an oncoprotein, upregulates the expression of various enzymes involved in cholesterol metabolism. The overexpression of MUC1 has been found to be correlated with TAM resistance and poor survival. Cholesteryl esters of oleic and stearic acids are responsible for the proliferation and invasiveness of tumors. MUC1 upregulates the expression of the ACAT enzyme, therefore inhibition of cancer cell growth by TAM is minimized leading to resistance against it.

Key Molecule: Pyruvate kinase M2 (PKM)

[12]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 2.62E-40

Fold-change: 1.53E-01

Z-score: 1.50E+01

Experimental Note

Revealed Based on the Cell Line Data

Mechanism Description

Key Molecule: Cyclic AMP-responsive element-binding protein 1 (CREB1)

[16]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 3.55E-02

Fold-change: 1.23E-02

Z-score: 2.11E+00

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

SkBR3 cells

Breast

Homo sapiens (Human)

CVCL_0033

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

BT549 cells

Breast

Homo sapiens (Human)

CVCL_1092

MCF10A cells

Breast

Homo sapiens (Human)

CVCL_0598

In Vivo Model

Nude mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

MTT assay; Annexin V-FITC (fluorescein isothiocyanate)/PI analysis

Mechanism Description

Down-regulation of microRNA-27b-3p enhances tamoxifen resistance in breast cancer by increasing NR5A2 and CREB1 expression. Overexpression of NR5A2 and CREB1 reverses reduction of cell viability and induction of apoptosis by miR27b-3p mimics, and depletion of NR5A2 and CREB1 reverses induction of cell viability and reduction of apoptosis by miR509-5p inhibitors in tamoxifen-treated cells.

Key Molecule: Histone-lysine N-methyltransferase NSD2 (NSD2)

[17]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 1.57E-54

Fold-change: 1.07E-01

Z-score: 1.75E+01

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

ZR75-1 cells

Breast

Homo sapiens (Human)

CVCL_0588

293T cells

Breast

Homo sapiens (Human)

CVCL_0063

In Vivo Model

BALB/c nu/nu athymic mice xenografts model

Mus musculus

Experiment for
Drug Resistance

Cell death detection ELISA kit assay

Mechanism Description

NSD2 overexpression is significantly associated with high risk of relapse and poor survival in tamoxifen-treated ER-positive breast cancer patients. NSD2 drives tamoxifen therapy resistance through coordinated stimulation of key glucose metabolism enzymes and enhancement of the PPP.

Key Molecule: Solute carrier family 2 member 1 (SLC2A1)

[12]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 1.10E-51

Fold-change: 1.07E-01

Z-score: 1.63E+01

Experimental Note

Identified from the Human Clinical Data

Experiment for
Molecule Alteration

Immunohistochemical assay

Mechanism Description

Overexpression of GLUT1 has been reported in aggressive and malignant breast cancer and has been correlated with the poor prognosis. Increased expression of GLUT1 in the TAMR cells compared to the TAM-sensitive cells. knockdown of GLUT1 in TAMR MCF-7 cells resulted in increased expression of p62 protein and decreased levels of LC3B-II, leading to autophagy and cells becoming sensitive to TAM.

Key Molecule: Retinoblastoma-associated protein (RB1)

[18]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 9.73E-02

Fold-change: -1.02E-02

Z-score: -1.66E+00

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

BT474 cells

Breast

Homo sapiens (Human)

CVCL_0179

MCF7/TAMR cells

Breast

Homo sapiens (Human)

CVCL_EG55

CAMA-1 cells

Breast

Homo sapiens (Human)

CVCL_1115

HEK293 FT cells

Kidney

Homo sapiens (Human)

CVCL_6911

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

Promega assay

Mechanism Description

Tamoxifen-resistant cells express miRNA-519a at high levels, which directly represses the expression of PTEN, RB1, and CDkN1A, central nodes of a dense network, allowing the cells to proliferate, even in the presence of tamoxifen. miRNA-519a increases viability and S-phase population of the cell cycle, but does not affect EMT or invasion. miRNA-519a-expressing cells evade tamoxifen-induced apoptosis.

Key Molecule: Tumor protein p73 (TP73)

[19]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 6.09E-04

Fold-change: -1.83E-02

Z-score: -3.45E+00

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

Western blot analysis; RIP assay; Luciferase reporter assay

Experiment for
Drug Resistance

MTT assay; Flow cytometry assay

Mechanism Description

microRNA 663b mediates TAM resistance in breast cancer by downrerulating TP73 expression.

Key Molecule: Histone deacetylase 4 (HDAC4)

[22]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 1.48E-37

Fold-change: -1.85E-01

Z-score: -1.45E+01

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell invasion

Activation

hsa05200

Cell migration

Activation

hsa04670

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

MTT assay; Transwell assay

Mechanism Description

Over-expression of miR-10b in ER-positive MCF-7 and T47D cells led to increased resistance to tamoxifen and an attenuation of tamoxifen-mediated inhibition of migration, whereas down-regulation of miR-10b in MCF7TR cells resulted in increased sensitivity to tamoxifen. Luciferase assays identified HDAC4 as a direct target of miR-10b. In MCF7TR cells, we observed down-regulation of HDAC4 by miR-10b. HDAC4-specific siRNA-mediated inactivation of HDAC4 in MCF-7 cells led to acquisition of tamoxifen resistance, and, moreover, reduction of HDAC4 in MCF7TR cells by HDAC4-specific siRNA transfection resulted in further enhancement of tamoxifen-resistance.

Key Molecule: Forkhead box protein O3 (FOXO3)

[1]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell migration

Activation

hsa04670

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

In Vivo Model

BALB/c nude mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

Western blot analysis; RT-qPCR

Experiment for
Drug Resistance

MTT assay; Flow cytometry assay; Colony formation assay

Mechanism Description

FOXO3a is a direct target gene of miR-182-5p and is regulated by hsa_circ_0025202, tumor inhibition and tamoxifen sensitization effects of hsa_circ_0025202 were achieved via the miR-182-5p/FOXO3a axis.

Key Molecule: Estrogen receptor alpha (ESR1)

[35]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

ER-alpha signaling pathway

Inhibition

hsa04915

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

Crystal Violet Assay

Mechanism Description

microRNA-335-5p and -3p synergize to inhibit estrogen receptor alpha expression and promote tamoxifen resistance. MiRNA duplex repressed genes involved in the ERalpha signaling pathway, and enhanced resistance of MCF-7 cells to the growth inhibitory effects of tamoxifen.

Key Molecule: Long transient receptor potential 2 (TRPM2)

[16]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

SkBR3 cells

Breast

Homo sapiens (Human)

CVCL_0033

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

BT549 cells

Breast

Homo sapiens (Human)

CVCL_1092

MCF10A cells

Breast

Homo sapiens (Human)

CVCL_0598

In Vivo Model

Nude mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

MTT assay; Annexin V-FITC (fluorescein isothiocyanate)/PI analysis

Mechanism Description

Key Molecule: Ribonuclease P protein subunit p21 (RPP21)

[36]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Methylation

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell viability

Activation

hsa05200

PI3K/AKT signaling pathway

Activation

hsa04151

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

LCC2 cells

Breast

Homo sapiens (Human)

CVCL_DP51

LCC9 cells

Breast

Homo sapiens (Human)

CVCL_DP52

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

WST-1 assay; Flow cytometry assay

Mechanism Description

UCA1 was physically associated with the enhancer of zeste homolog 2 (EZH2), which suppressed the expression of p21 through histone methylation (H3k27me3) on the p21 promoter and the induced overexpression of UCA1 decreased the drug sensitivity of tamoxifen.

Key Molecule: Suppressor of cytokine signaling 6 (SOCS6)

[37]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

SOCS6/STAT3 signaling pathway

Regulation

N.A.

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

SkBR3 cells

Breast

Homo sapiens (Human)

CVCL_0033

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Inhibition of miR-155 sensitizes breast cancer cells to tamoxifen and SOCS6 sensitizes the cells to tamoxifen.

Key Molecule: Cyclin-dependent kinase inhibitor 1A (CDKN1A)

[18]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

BT474 cells

Breast

Homo sapiens (Human)

CVCL_0179

MCF7/TAMR cells

Breast

Homo sapiens (Human)

CVCL_EG55

CAMA-1 cells

Breast

Homo sapiens (Human)

CVCL_1115

HEK293 FT cells

Kidney

Homo sapiens (Human)

CVCL_6911

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

Promega assay

Mechanism Description

Key Molecule: Phosphatase and tensin homolog (PTEN)

[18]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

BT474 cells

Breast

Homo sapiens (Human)

CVCL_0179

MCF7/TAMR cells

Breast

Homo sapiens (Human)

CVCL_EG55

CAMA-1 cells

Breast

Homo sapiens (Human)

CVCL_1115

HEK293 FT cells

Kidney

Homo sapiens (Human)

CVCL_6911

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

Promega assay

Mechanism Description

Key Molecule: Estrogen receptor alpha (ESR1)

[39]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

ER-alpha 36 mediated nongenomic estrogen signaling pathway

Activation

hsa04915

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

SkBR3 cells

Breast

Homo sapiens (Human)

CVCL_0033

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

ZR75-1 cells

Breast

Homo sapiens (Human)

CVCL_0588

MDA-MB-436 cells

Breast

Homo sapiens (Human)

CVCL_0623

MDA-MB-468 cells

Breast

Homo sapiens (Human)

CVCL_0419

184A1 cells

Breast

Homo sapiens (Human)

CVCL_3040

HB3396 cells

Breast

Homo sapiens (Human)

N.A.

MEGM cells

Breast

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

Luciferase assay

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Breast cancer patients with tumors highly expressing ER-alpha36 benefit less from tamoxifen treatment. Both mRNA and protein expression of ER-alpha36 were inhibited by let-7 mimics and enhanced by let-7 inhibitors. Our results suggested a novel regulatory mechanism of let-7 miRNAs on ER-alpha36 mediated nongenomic estrogen signal pathways and Tam resistance.

Key Molecule: Estrogen receptor alpha (ESR1)

[39]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

ER-alpha 36 mediated nongenomic estrogen signaling pathway

Activation

hsa04915

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

SkBR3 cells

Breast

Homo sapiens (Human)

CVCL_0033

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

ZR75-1 cells

Breast

Homo sapiens (Human)

CVCL_0588

MDA-MB-436 cells

Breast

Homo sapiens (Human)

CVCL_0623

MDA-MB-468 cells

Breast

Homo sapiens (Human)

CVCL_0419

184A1 cells

Breast

Homo sapiens (Human)

CVCL_3040

HB3396 cells

Breast

Homo sapiens (Human)

N.A.

MEGM cells

Breast

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

Luciferase assay

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Key Molecule: Cyclin-dependent kinase inhibitor 1B (CDKN1B)

[2]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Ectopic expression of miR-221/222 rendered the parental MCF-7 cells resistant to tamoxifen. The protein level of the cell cycle inhibitor p27kip1, a known target of miR-221/222, was reduced by 50% in OHTR cells and by 28-50% in miR-221/222-overexpressing MCF-7 cells. Furthermore, overexpression of p27kip1 in the resistant OHTR cells caused enhanced cell death when exposed to tamoxifen.

Key Molecule: Mediator of RNA polymerase II transcription subunit 1 (MED1)

[47]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Missense mutation

p.S1179X

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

AXLK signaling pathway

Activation

hsa01521

In Vitro Model

Plasma

Blood

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

Circulating-free DNA assay; Whole exome sequencing assay

Mechanism Description

Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Serine-protein kinase ATM (ATM)

[47]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Missense mutation

p.I2948F

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

AXLK signaling pathway

Activation

hsa01521

In Vitro Model

Plasma

Blood

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

Circulating-free DNA assay; Whole exome sequencing assay

Mechanism Description

Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA)

[47]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Missense mutation

p.D714E

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Angiogenic potential

Inhibition

hsa04370

In Vitro Model

Plasma

Blood

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

Circulating-free DNA assay; Whole exome sequencing assay

Mechanism Description

Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Hexokinase-2 (HK2)

[12]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Mechanism Description

Key Molecule: Renal carcinoma antigen NY-REN-56 (PFKFB3)

[12]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Mechanism Description

Key Molecule: N-6 adenine-specific DNA methyltransferase 1 (N6AMT1)

[48]

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

PI3K/AKT signaling pathway

Activation

hsa04151

In Vitro Model

MCF-7 TamR cells

Breast

Homo sapiens (Human)

CVCL_0031

T47D TamR cells

Breast

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

Western blot assay; qRT-PCR

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

We discover, via bioinformatics analysis and clinical samples, that N6 adenine-specific DNA methyltransferase 1 (N6AMT1) is highly expressed in luminal breast cancer but downregulated in tamoxifen-resistant (TamR) BC cells. ChIP-qPCR and luciferase reporter assays showed that FOXA1 binds to the N6AMT1 promoter and enhances its transcription. In TamR models, FOXA1 and N6AMT1 are downregulated, increasing p110alpha protein levels (but not mRNA), phospho-AKT levels, and tamoxifen resistance. In vivo, N6AMT1 overexpression enhanced tamoxifen sensitivity, while knockdown reduced it; this sensitivity could be restored with the p110alpha inhibitor A66.

Key Molecule: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3)

[49]

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

M2000T

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF-7/TamR cells

Breast

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

CCK8 assay; Colony formation assay; Annexin V-propidium iodide staining assay

Mechanism Description

Aerobic glycolysis, a metabolic process, has been implicated in chemotherapeutic resistance. In this study, we demonstrate that elevated glycolysis plays a central role in TAM resistance and can be effectively targeted and overcome by Rg3. Mechanistically, we observed upregulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key mediator of glycolysis, in TAM-resistant MCF-7/TamR and T-47D/TamR cells. Crucially, PFKFB3 is indispensable for the synergistic effect of TAM and Rg3 combination therapy, which suppresses cell proliferation and glycolysis in MCF-7/TamR and T-47D/TamR cells, both in vitro and in vivo. Moreover, overexpression of PFKFB3 in MCF-7 cells mimicked the TAM resistance phenotype. Importantly, combination treatment significantly reduced TAM-resistant MCF-7 cell proliferation in an in vivo model.

Key Molecule: Nuclear receptor subfamily 6 group A member 1 (NR6A1)

[42]

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

NR6A1/DNMT3A signaling pathway

Regulation

N.A.

In Vitro Model

MCF7 cells

Breast

Homo sapiens (Human)

CVCL_0031

MDA-MB-231cells

Breast

Homo sapiens (Human)

CVCL_0062

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

MTS assay; Immunoblotting assay assay

Mechanism Description

Resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A.Suppresses ERalpha activity, induces partial resistance to rapamycin and tamoxifen, and slightly decreases DNMT3A expression, indicating a functional interplay between NR6A1 and DNMT3A signaling. The development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes.

Key Molecule: Nuclear receptor subfamily 6 group A member 1 (NR6A1)

[42]

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

DNMT3A signaling pathway

Regulation

N.A.

In Vitro Model

MCF-7/T cells

Breast

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Our findings indicate that the development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. We demonstrated the critical role of NR6A1 downregulation in resistance development. Additionally, we observed activation of Snail - a key regulator in the epithelial-mesenchymal transition - as a mediator of the effects of NR6A1 depletion, establishing a direct link between Snail expression and resistance formation.

Key Molecule: Nuclear receptor subfamily 6 group A member 1 (NR6A1)

[42]

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

DNMT3A signaling pathway

Regulation

N.A.

In Vitro Model

MDA-MB-231cells

Breast

Homo sapiens (Human)

CVCL_0062

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Regulation by the Disease Microenvironment (RTDM)

Click to Show/Hide

Key Molecule: High mobility group protein B3 (HMGB3)

[14]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 4.35E-212

Fold-change: 3.28E-01

Z-score: 4.32E+01

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell invasion

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

Dual luciferase; Western blot analysis

Experiment for
Drug Resistance

Transwell assay; Promega assay

Mechanism Description

miR-27b is epigenetically downregulated in tamoxifen resistant breast cancer cells due to promoter methylation and regulates tamoxifen sensitivity by targeting HMGB3.

Key Molecule: Protein LYRIC (MTDH)

[3]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Differential expression of the molecule in resistant disease

Classification of Disease

Breast cancer [ICD-11: 2C60]

The Specified Disease

Breast cancer

The Studied Tissue

Breast tissue

The Expression Level of Disease Section Compare with the Healthy Individual Tissue

p-value: 2.31E-53

Fold-change: 1.10E-01

Z-score: 1.82E+01

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Cell migration

Activation

hsa04670

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

Cell titer glo assay

Mechanism Description

Overexpression of MTDH increased mesenchymal markers while downregulating E-cadherin expression, associated with poor prognosis and increased risk of metastasis in breast cancer. Tamoxifen-sensitive cells expressing miRNA-375 at high levels directly represses MTDH expression, and that this regulation confers the cells with a tamoxifen sensitive and epithelial phenotype.

Key Molecule: hsa-mir-205

[46]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell invasion

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

HEK293T cells

Kidney

Homo sapiens (Human)

CVCL_0063

MCF10A cells

Breast

Homo sapiens (Human)

CVCL_0598

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

In MDA-MB-231 cells, down-regulated LncRNA-ROR could inhibit the EMT of breast cancer cells and enhance the sensibility of breast cancer cells to tamoxifen by increasing miR205 expression and suppressing the expressions of ZEB1 and ZEB2.

Key Molecule: Long non-protein coding RNA, regulator of reprogramming (LINC-ROR)

[46]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell invasion

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

HEK293T cells

Kidney

Homo sapiens (Human)

CVCL_0063

MCF10A cells

Breast

Homo sapiens (Human)

CVCL_0598

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

Key Molecule: hsa-mir-27b

[14]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell invasion

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

Transwell assay; Promega assay

Mechanism Description

miR-27b is epigenetically downregulated in tamoxifen resistant breast cancer cells due to promoter methylation and regulates tamoxifen sensitivity by targeting HMGB3.

Key Molecule: hsa-mir-375

[3]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Cell migration

Activation

hsa04670

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

Cell titer glo assay

Mechanism Description

Aberration of the Drug's Therapeutic Target (ADTT)

Click to Show/Hide

Key Molecule: Estrogen receptor alpha (ESR1)

[23], [24], [25]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Missense mutation

p.Y537S

Molecule Info

Wild Type Structure

Method: X-ray diffraction

Resolution: 1.60 Å

PDB: 2IOG

Mutant Type Structure

Method: X-ray diffraction

Resolution: 1.50 Å

PDB: 5DXE

Download The Information of Sequence

Download The Structure File

Click to Show/Hide the Structure

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

PI3K signaling pathway

Activation

hsa04151

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Whole-exome sequencing assay; SNP Array profiling assay

Experiment for
Drug Resistance

Tumor biopsy assay

Mechanism Description

Mutations in ESR1 were detected in 4% of cancers and clustered in the ligand-binding domain. These included p.Tyr537(Cys/Asn/Ser) mutations (three patients) that have been shown to cause constitutive activation and resistance to tamoxifen therapy in breast cancer.

Key Molecule: Estrogen receptor alpha (ESR1)

[24]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Missense mutation

p.D538G

Molecule Info

Wild Type Structure

Method: X-ray diffraction

Resolution: 1.60 Å

PDB: 2IOG

Mutant Type Structure

Method: X-ray diffraction

Resolution: 1.90 Å

PDB: 4PXM

Download The Information of Sequence

Download The Structure File

Click to Show/Hide the Structure

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Next-generation sequencing assay

Mechanism Description

In our analysis of frequently mutated oncogenes and tumor suppressors, ESR1 mutations stood out as a common and plausible event that could contribute to resistance. We found that the mutations in both Tyr537 and Asp538 strongly promoted ER signaling in absence of ligand. This was observed biochemically as increased phosphorylation on S118, increased association with AIB1, and diminished sensitivity to HSP90 inhibitors. Functionally, the mutations in vitro promoted the expression of classical ER target genes in the absence of hormone.

Key Molecule: Estrogen receptor alpha (ESR1)

[23], [25], [26]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Missense mutation

p.D538G

Molecule Info

Wild Type Structure

Method: X-ray diffraction

Resolution: 1.60 Å

PDB: 2IOG

Mutant Type Structure

Method: X-ray diffraction

Resolution: 1.90 Å

PDB: 4PXM

Download The Information of Sequence

Download The Structure File

Click to Show/Hide the Structure

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Circulating cell-free DNA assay; Liquid biopsy assay; Droplet digital PCR assay; Next generation assay

Experiment for
Drug Resistance

Progression-free survival assay; Overall survival assay

Mechanism Description

Recent studies have also highlighted the utility of ex vivo culturing of CTCs as a method of individualized drug susceptibility testing. Using this method, the authors found that CTCs have various mutations (including the p.D538G and p.Y537S ESR1 mutations), and showed that low-dose administration of the HSP90 inhibitor STA9090 alone or in combination with raloxifene and fulvestrant has growth-inhibitory effects.

Key Molecule: Estrogen receptor alpha (ESR1)

[27]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Missense mutation

p.L536_D538>P

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Next-generation sequencing assay

Experiment for
Drug Resistance

Overall survival assay

Mechanism Description

All 28 patients were found to harbor ESR1 mutations affecting ligand-binding domain with the most common mutations affecting Y537 (17/28, 60.7%) and D538 (9/28, 32.1%). ESR1 mutation was found in 12.1% of a large cohort of advanced breast cancer patients. Exemestane in combination with everolimus might be a reasonable option. Prospective studies are warranted to validate these findings.

Key Molecule: Estrogen receptor alpha (ESR1)

[24], [28], [29]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Missense mutation

p.Y537N

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

PI3K signaling pathway

Activation

hsa04151

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Whole-exome sequencing assay; SNP Array profiling assay

Experiment for
Drug Resistance

Tumor biopsy assay

Mechanism Description

Key Molecule: Estrogen receptor alpha (ESR1)

[24], [29], [30]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Missense mutation

p.Y537C

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

PI3K signaling pathway

Activation

hsa04151

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Whole-exome sequencing assay; SNP Array profiling assay

Experiment for
Drug Resistance

Tumor biopsy assay

Mechanism Description

Key Molecule: Estrogen receptor alpha (ESR1)

[23]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Missense mutation

p.L536Q

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Whole-genome sequencing assay

Mechanism Description

Whole-exome and transcriptome analysis showed that six cases harbored mutations of ESR1 affecting its ligand-binding domain (LBD), all of whom had been treated with anti-estrogens and estrogen deprivation therapies.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Click to Show/Hide

Key Molecule: hsa_circ_0025202

[1]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell migration

Activation

hsa04670

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

In Vivo Model

BALB/c nude mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

MTT assay; Flow cytometry assay; Colony formation assay

Mechanism Description

Hsa_circ_0025202 suppressed BC progression and sensitized cells to TAM via sponging miR-182-5p, thereby attenuating its oncogenic effect.

Key Molecule: hsa-miR-182-5p

[1]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell migration

Activation

hsa04670

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

In Vivo Model

BALB/c nude mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

MTT assay; Flow cytometry assay; Colony formation assay

Mechanism Description

Hsa_circ_0025202 suppressed BC progression and sensitized cells to TAM via sponging miR-182-5p, thereby attenuating its oncogenic effect.

Key Molecule: ADAMTS9 antisense RNA 2 (ADAMTS9-AS2)

[31]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

CCK8 assay; Flow cytometry assay

Mechanism Description

Downregulated LncRNA ADAMTS9-AS2 in breast cancer enhances tamoxifen resistance by activating microRNA-130a-5p.

Key Molecule: hsa-miR-130a-5p

[31]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

RT-qPCR

Experiment for
Drug Resistance

CCK8 assay; Flow cytometry assay

Mechanism Description

Downregulated LncRNA ADAMTS9-AS2 in breast cancer enhances tamoxifen resistance by activating microRNA-130a-5p.

Key Molecule: Urothelial cancer associated 1 (UCA1)

[13], [32], [33]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell viability

Activation

hsa05200

mTOR signaling pathway

Activation

hsa04150

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

BT474 cells

Breast

Homo sapiens (Human)

CVCL_0179

LCC2 cells

Breast

Homo sapiens (Human)

CVCL_DP51

LCC9 cells

Breast

Homo sapiens (Human)

CVCL_DP52

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

CCK8 assay; Soft agar colony formation assay; Flow cytometry assay

Mechanism Description

Long non-coding RNA UCA1 enhances tamoxifen resistance in ER positive breast cancer cells through a miR18a-HIF1alpha feedback regulatory loop.

Key Molecule: Long non-protein coding RNA, regulator of reprogramming (LINC-ROR)

[34]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

MAPK/ERK signaling pathway

Activation

hsa04011

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

RoR kO cells

Breast

Homo sapiens (Human)

N.A.

GRNA control cells

Breast

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Linc-RoR causes the upregulation of phosphorylated MAPk/ERk pathway which in turn activates ER signaling. Linc-RoR promotes estrogen-independent growth and activation of MAPk/ERk pathway of breast cancer cells by regulating the ERk-specific phosphatase DUSP7.

Key Molecule: hsa-mir-18a

[33]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell viability

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

BT474 cells

Breast

Homo sapiens (Human)

CVCL_0179

LCC2 cells

Breast

Homo sapiens (Human)

CVCL_DP51

LCC9 cells

Breast

Homo sapiens (Human)

CVCL_DP52

Experiment for
Molecule Alteration

qRT-PCR; Dual luciferase assay

Experiment for
Drug Resistance

CCK8 assay; Soft agar assay; Flow cytometric analysis

Mechanism Description

Key Molecule: hsa-miR-335-3p

[35]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

ER-alpha signaling pathway

Inhibition

hsa04915

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

Crystal Violet Assay

Mechanism Description

Key Molecule: hsa-miR-335-5p

[35]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

ER-alpha signaling pathway

Inhibition

hsa04915

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

Crystal Violet Assay

Mechanism Description

Key Molecule: hsa-miR-27b-3p

[16]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

SkBR3 cells

Breast

Homo sapiens (Human)

CVCL_0033

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

BT549 cells

Breast

Homo sapiens (Human)

CVCL_1092

MCF10A cells

Breast

Homo sapiens (Human)

CVCL_0598

In Vivo Model

Nude mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

RT-PCR

Experiment for
Drug Resistance

MTT assay; Annexin V-FITC (fluorescein isothiocyanate)/PI analysis

Mechanism Description

Key Molecule: Urothelial cancer associated 1 (UCA1)

[36]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell viability

Activation

hsa05200

PI3K/AKT signaling pathway

Activation

hsa04151

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

LCC2 cells

Breast

Homo sapiens (Human)

CVCL_DP51

LCC9 cells

Breast

Homo sapiens (Human)

CVCL_DP52

Experiment for
Molecule Alteration

RT-PCR,RT-qPCR

Experiment for
Drug Resistance

WST-1 assay; Flow cytometry assay

Mechanism Description

Key Molecule: hsa-miR-449a

[9]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Cell viability

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

Decreased miR-449a causes the upregulation of ADAM22, which induces tamoxifen resistance of breast cancer cells.

Key Molecule: hsa-mir-26a

[15]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell viability

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

SkBR3 cells

Breast

Homo sapiens (Human)

CVCL_0033

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

BT474 cells

Breast

Homo sapiens (Human)

CVCL_0179

Hs-578T cells

Breast

Homo sapiens (Human)

CVCL_0332

Experiment for
Molecule Alteration

RT-qPCR

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Both miR-26a knockdown and E2F7 overexpression conferred resistance to TAM in MCF-7 cells and there is an inverse correlation between miR-26a and E2F7 expression.

Key Molecule: hsa-miR-663b

[19]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

RT-qPCR

Experiment for
Drug Resistance

MTT assay; Flow cytometry assay

Mechanism Description

microRNA 663b mediates TAM resistance in breast cancer by downrerulating TP73 expression.

Key Molecule: hsa-mir-155

[37]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

SOCS6/STAT3 signaling pathway

Regulation

N.A.

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

SkBR3 cells

Breast

Homo sapiens (Human)

CVCL_0033

In Vivo Model

Nude mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Inhibition of miR-155 sensitizes breast cancer cells to tamoxifen and SOCS6 sensitizes the cells to tamoxifen.

Key Molecule: HOX transcript antisense RNA (HOTAIR)

[38]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell invasion

Activation

hsa05200

ER signaling pathway

Activation

hsa04915

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

WST1 assay

Mechanism Description

HOTAIR overexpression increases breast cancer cell proliferation, whereas its depletion significantly impairs cell survival and abolishes tamoxifen-resistant cell growth. The LncRNA HOTAIR is directly repressed by ER and its up-regulation promotes ligand-independent ER activities and contributes to tamoxifen resistance.

Key Molecule: hsa-mir-10b

[22]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell invasion

Activation

hsa05200

Cell migration

Activation

hsa04670

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

Experiment for
Molecule Alteration

RT-qPCR

Experiment for
Drug Resistance

MTT assay; Transwell assay

Mechanism Description

Key Molecule: hsa-mir-519a

[18]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell proliferation

Activation

hsa05200

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

BT474 cells

Breast

Homo sapiens (Human)

CVCL_0179

MCF7/TAMR cells

Breast

Homo sapiens (Human)

CVCL_EG55

CAMA-1 cells

Breast

Homo sapiens (Human)

CVCL_1115

HEK293 FT cells

Kidney

Homo sapiens (Human)

CVCL_6911

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

Promega assay

Mechanism Description

Key Molecule: hsa-let-7b

[39]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

ER-alpha 36 mediated nongenomic estrogen signaling pathway

Activation

hsa04915

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

SkBR3 cells

Breast

Homo sapiens (Human)

CVCL_0033

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

ZR75-1 cells

Breast

Homo sapiens (Human)

CVCL_0588

MDA-MB-436 cells

Breast

Homo sapiens (Human)

CVCL_0623

MDA-MB-468 cells

Breast

Homo sapiens (Human)

CVCL_0419

184A1 cells

Breast

Homo sapiens (Human)

CVCL_3040

HB3396 cells

Breast

Homo sapiens (Human)

N.A.

MEGM cells

Breast

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Key Molecule: hsa-let-7i

[39]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

ER-alpha 36 mediated nongenomic estrogen signaling pathway

Activation

hsa04915

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

SkBR3 cells

Breast

Homo sapiens (Human)

CVCL_0033

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

T47D cells

Breast

Homo sapiens (Human)

CVCL_0553

ZR75-1 cells

Breast

Homo sapiens (Human)

CVCL_0588

MDA-MB-436 cells

Breast

Homo sapiens (Human)

CVCL_0623

MDA-MB-468 cells

Breast

Homo sapiens (Human)

CVCL_0419

184A1 cells

Breast

Homo sapiens (Human)

CVCL_3040

HB3396 cells

Breast

Homo sapiens (Human)

N.A.

MEGM cells

Breast

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Key Molecule: hsa-mir-342

[4]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

qRT-PCR; Northern blotting analysis

Experiment for
Drug Resistance

MTS assay

Mechanism Description

miR-342 regulates expression of genes involved in tamoxifen mediated tumor cell apoptosis and cell cycle progression.

Key Molecule: Breast cancer anti-estrogen resistance 4 (BCAR4)

[40]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

ERBB2/ERBB3 signaling pathway

Activation

hsa04012

In Vitro Model

ZR75-1 cells

Breast

Homo sapiens (Human)

CVCL_0588

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

Response evaluation criteria in solid tumors assay

Mechanism Description

In BCAR4-expressing cells, phosphorylation of v-erb-b2 erythroblastic leukaemia viral oncogene homolog (ERBB) 2, ERBB3, and their downstream mediators extracellular signal-regulated kinase 1/2 and v-akt murine thymoma viral oncogene homolog (AkT) 1/2, was increased. Selective knockdown of ERBB2 or ERBB3 inhibited proliferation, confirming their role in BCAR4-induced tamoxifen resistance.

Key Molecule: hsa-mir-221

[2]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

RT-PCR

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Key Molecule: hsa-mir-222

[2]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vitro Model

MCF-7 cells

Breast

Homo sapiens (Human)

CVCL_0031

Experiment for
Molecule Alteration

RT-PCR

Experiment for
Drug Resistance

MTT assay

Mechanism Description

Key Molecule: Arylamine N-acetyltransferase 1 (NAT1)

[41]

Resistant Disease

Breast cancer [ICD-11: 2C60.3]

Disease Info

Molecule Alteration

Epigenetic modification

Methylation aberrance

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Experiment for
Molecule Alteration

Bisulfite genomic sequencing assay; Methylation-specific PCR assay

Mechanism Description

Taken together, the higher methylation rate of the NAT1 gene is related to tamoxifen resistance, and this fact supports the hypothesis that hypermethylation of the NAT1 gene might affect the initiation of tamoxifen resistance.

Key Molecule: Nuclear receptor subfamily 6 group A member 1 (NR6A1)

[42]

Resistant Disease

Breast adenocarcinoma [ICD-11: 2C60.1]

Disease Info

Molecule Alteration

Epigenetic modification

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

MCF7 cells

Breast

Homo sapiens (Human)

CVCL_0031

MDA-MB-231cells

Breast

Homo sapiens (Human)

CVCL_0062

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

MTS assay; Immunoblotting assay assay

Mechanism Description

Ovarian cancer [ICD-11: 2C73]

Click to Show/Hide

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Protein LYRIC (MTDH)				[3]
Resistant Disease	Ovarian cancer [ICD-11: 2C73.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Ovarian cancer [ICD-11: 2C73]
The Specified Disease	Ovarian cancer
The Studied Tissue	Ovarian tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.25E-03 Fold-change: 9.64E-02 Z-score: 3.90E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell migration		Activation	hsa04670
In Vitro Model	OVCAR5 cells	Ovary	Homo sapiens (Human)	CVCL_1628
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Cell titer glo assay
Mechanism Description	Overexpression of MTDH increased mesenchymal markers while downregulating E-cadherin expression, associated with poor prognosis and increased risk of metastasis in breast cancer. Tamoxifen-sensitive cells expressing miRNA-375 at high levels directly represses MTDH expression, and that this regulation confers the cells with a tamoxifen sensitive and epithelial phenotype.
Key Molecule: hsa-mir-375				[3]
Resistant Disease	Ovarian cancer [ICD-11: 2C73.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell migration		Activation	hsa04670
In Vitro Model	OVCAR5 cells	Ovary	Homo sapiens (Human)	CVCL_1628
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Cell titer glo assay
Mechanism Description	Overexpression of MTDH increased mesenchymal markers while downregulating E-cadherin expression, associated with poor prognosis and increased risk of metastasis in breast cancer. Tamoxifen-sensitive cells expressing miRNA-375 at high levels directly represses MTDH expression, and that this regulation confers the cells with a tamoxifen sensitive and epithelial phenotype.

Lung cancer [ICD-11: 2C25]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Protein LYRIC (MTDH)				[3]
Resistant Disease	Lung cancer [ICD-11: 2C25.5]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Lung cancer [ICD-11: 2C25]
The Specified Disease	Lung cancer
The Studied Tissue	Lung tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.83E-11 Fold-change: 2.75E-02 Z-score: 6.93E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell migration		Activation	hsa04670
In Vitro Model	H1299 cells	Lung	Homo sapiens (Human)	CVCL_0060
	H1703 cells	Lung	Homo sapiens (Human)	CVCL_1490
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Cell titer glo assay
Mechanism Description	Overexpression of MTDH increased mesenchymal markers while downregulating E-cadherin expression, associated with poor prognosis and increased risk of metastasis in breast cancer. Tamoxifen-sensitive cells expressing miRNA-375 at high levels directly represses MTDH expression, and that this regulation confers the cells with a tamoxifen sensitive and epithelial phenotype.
Key Molecule: hsa-mir-375				[3]
Resistant Disease	Lung cancer [ICD-11: 2C25.5]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell migration		Activation	hsa04670
In Vitro Model	H1299 cells	Lung	Homo sapiens (Human)	CVCL_0060
	H1703 cells	Lung	Homo sapiens (Human)	CVCL_1490
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Cell titer glo assay
Mechanism Description	Overexpression of MTDH increased mesenchymal markers while downregulating E-cadherin expression, associated with poor prognosis and increased risk of metastasis in breast cancer. Tamoxifen-sensitive cells expressing miRNA-375 at high levels directly represses MTDH expression, and that this regulation confers the cells with a tamoxifen sensitive and epithelial phenotype.

Breast invasive carcinoma [ICD-11: 2C61]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Metabolic Reprogramming via Altered Pathways (MRAP)		Click to Show/Hide
Key Molecule: Neurofibromin 1 (NF1)			[60]
Metabolic Type	Lipid metabolism
Sensitive Disease	ER+ breast adenocarcinoma [ICD-11: 2C61.1]		Disease Info
Molecule Alteration	Mutation	.	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vivo Model	Rat, with ER + MCF7 cell lines		Rats
Experiment for Molecule Alteration	LC-MS
Experiment for Drug Resistance	Incucyte proliferation assay
Mechanism Description	Lastly,NF1deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis.

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Prof. Feng ZHU (zhufeng@zju.edu.cn)