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
• Indication:
  In total 1 Indication(s)
  Breast cancer [ICD-11: 2C60]; Approved; [1]
• 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]
• 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

  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

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-375 [3]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• 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
• In Vitro Model: 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.

Key Molecule: Protein LYRIC (MTDH) [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• 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
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• Experiment for Molecule Alteration: Western blotting 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.

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Estrogen receptor alpha (ESR1) [5]

• Molecule Alteration: Missense mutation; p.L536_D538>P
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [6]

• Molecule Alteration: Missense mutation; p.D538G
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [6], [7], [8]

• Molecule Alteration: Missense mutation; p.Y537S
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [6], [9], [10]

• Molecule Alteration: Missense mutation; p.Y537N
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [6], [10], [11]

• Molecule Alteration: Missense mutation; p.Y537C
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [7], [8], [12]

• Molecule Alteration: Missense mutation; p.D538G
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [7]

• Molecule Alteration: Missense mutation; p.L536Q
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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)

Key Molecule: hsa_circ_0025202 [1]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: 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]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: 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) [13]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Downregulated LncRNA ADAMTS9-AS2 in breast cancer enhances tamoxifen resistance by activating microRNA-130a-5p.

Key Molecule: hsa-miR-130a-5p [13]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: 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) [14], [15], [16]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: LCC2 cells; Breast; Homo sapiens (Human); CVCL_DP51
• In Vitro Model: 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) [17]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: RoR kO cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: 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 [16]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: LCC2 cells; Breast; Homo sapiens (Human); CVCL_DP51
• In Vitro Model: 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: 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: hsa-miR-335-3p [18]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: 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: hsa-miR-335-5p [18]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: 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: hsa-miR-27b-3p [19]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: 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: 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: Urothelial cancer associated 1 (UCA1) [20]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: LCC2 cells; Breast; Homo sapiens (Human); CVCL_DP51
• In Vitro Model: 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: 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: hsa-miR-449a [21]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: 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 [22]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: 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 [23]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: 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 [24]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: SOCS6/STAT3 signaling pathway; Regulation; hsa04630
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: 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) [25]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: ER signaling pathway; Activation; hsa04915
• 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: 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 [26]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• 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: RT-qPCR
• 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: hsa-mir-519a [27]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MCF7/TAMR cells; Breast; Homo sapiens (Human); CVCL_EG55
• In Vitro Model: CAMA-1 cells; Breast; Homo sapiens (Human); CVCL_1115
• In Vitro Model: HEK293 FT cells; Kidney; Homo sapiens (Human); CVCL_6911
• Experiment for Molecule Alteration: qRT-PCR
• 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: hsa-let-7b [28]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: 184A1 cells; Breast; Homo sapiens (Human); CVCL_3040
• In Vitro Model: HB3396 cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: MEGM cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• 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: hsa-let-7i [28]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: 184A1 cells; Breast; Homo sapiens (Human); CVCL_3040
• In Vitro Model: HB3396 cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: MEGM cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• 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: hsa-mir-342 [4]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [29]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: 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: hsa-mir-222 [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: 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: Arylamine N-acetyltransferase 1 (NAT1) [30]

• Molecule Alteration: Epigenetic modification; Methylation aberrance
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-205 [31]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 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) [31]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 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: High mobility group protein B3 (HMGB3) [32]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: hsa-mir-27b [32]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: 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: 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: Protein LYRIC (MTDH) [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: Western blotting 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Forkhead box protein O3 (FOXO3) [1]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: 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) [18]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Cyclic AMP-responsive element-binding protein 1 (CREB1) [19]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: 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: Long transient receptor potential 2 (TRPM2) [19]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT549 cells; Breast; Homo sapiens (Human); CVCL_1092
• In Vitro Model: 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: Hypoxia-inducible factor 1-alpha (HIF1A) [14]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: LCC2 cells; Breast; Homo sapiens (Human); CVCL_DP51
• In Vitro Model: 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: Ribonuclease P protein subunit p21 (RPP21) [20]

• Molecule Alteration: Methylation; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: LCC2 cells; Breast; Homo sapiens (Human); CVCL_DP51
• In Vitro Model: 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: Metalloproteinase-disintegrin ADAM22-3 (ADAM22) [21]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: 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: Transcription factor E2F7 (E2F7) [22]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: 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: Tumor protein p73 (TP73) [23]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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; 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: Suppressor of cytokine signaling 6 (SOCS6) [24]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: SOCS6/STAT3 signaling pathway; Regulation; hsa04630
• 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: MTT assay
• Mechanism Description: Inhibition of miR-155 sensitizes breast cancer cells to tamoxifen and SOCS6 sensitizes the cells to tamoxifen.

Key Molecule: Histone deacetylase 4 (HDAC4) [26]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• 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: 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: Cyclin-dependent kinase inhibitor 1A (CDKN1A) [27]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MCF7/TAMR cells; Breast; Homo sapiens (Human); CVCL_EG55
• In Vitro Model: CAMA-1 cells; Breast; Homo sapiens (Human); CVCL_1115
• In Vitro Model: 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: Phosphatase and tensin homolog (PTEN) [27]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MCF7/TAMR cells; Breast; Homo sapiens (Human); CVCL_EG55
• In Vitro Model: CAMA-1 cells; Breast; Homo sapiens (Human); CVCL_1115
• In Vitro Model: 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: Retinoblastoma-associated protein (RB1) [27]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MCF7/TAMR cells; Breast; Homo sapiens (Human); CVCL_EG55
• In Vitro Model: CAMA-1 cells; Breast; Homo sapiens (Human); CVCL_1115
• In Vitro Model: 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: Estrogen receptor alpha (ESR1) [28]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: 184A1 cells; Breast; Homo sapiens (Human); CVCL_3040
• In Vitro Model: HB3396 cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: 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) [28]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: 184A1 cells; Breast; Homo sapiens (Human); CVCL_3040
• In Vitro Model: HB3396 cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: 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: Cyclin-dependent kinase inhibitor 1B (CDKN1B) [2]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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 blotting 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) [33]

• Molecule Alteration: Missense mutation; p.S1179X
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [33]

• Molecule Alteration: Missense mutation; p.I2948F
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [33]

• Molecule Alteration: Missense mutation; p.D714E
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Alpha-enolase (ENO1) [34]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Solute carrier family 2 member 1 (SLC2A1) [34]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Hexokinase-2 (HK2) [34]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Mucin-1 (MUC1) [34]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Renal carcinoma antigen NY-REN-56 (PFKFB3) [34]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Pyruvate kinase M2 (PKM) [34]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Ribonucleoside-diphosphate reductase subunit M2 (RRM2) [34]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Histone-lysine N-methyltransferase NSD2 (NSD2) [35]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: 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.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-130a-5p [13]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [36]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: ER positive breast cancer [ICD-11: 2C60.6]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: LCC2 cells; Breast; Homo sapiens (Human); CVCL_DP51
• In Vitro Model: 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) [37]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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 [38]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: MCF7/TAMR cells; Breast; Homo sapiens (Human); CVCL_EG55
• In Vitro Model: 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 [38]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: MCF7/TAMR cells; Breast; Homo sapiens (Human); CVCL_EG55
• In Vitro Model: 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) [39]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: 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 [40]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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 [41]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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 [42]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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 [42]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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 [43]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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 [44]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Regulation; hsa04150
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: 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 [45]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Regulation; 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: 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 [46]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: 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 [47]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: 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 [48]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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 [48]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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 [28]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: 184A1 cells; Breast; Homo sapiens (Human); CVCL_3040
• In Vitro Model: HB3396 cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: 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 [28]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: 184A1 cells; Breast; Homo sapiens (Human); CVCL_3040
• In Vitro Model: HB3396 cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: 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 [49]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: 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 [49]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: 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.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-205 [31]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 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) [31]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 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) [31]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 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) [31]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 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: Cadherin-1 (CDH1) [50]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: 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: H19, imprinted maternally expressed transcript (H19) [50]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [13]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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: B-cell lymphoma/leukemia 11A (BCL11A) [37]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [38]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: MCF7/TAMR cells; Breast; Homo sapiens (Human); CVCL_EG55
• In Vitro Model: 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) [40]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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: Homeobox protein Hox-B3 (HOXB3) [41]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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: CD166 antigen (ALCAM) [42]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [43]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [44]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Regulation; hsa04150
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: 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) [44]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Regulation; hsa04150
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: 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) [45]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Regulation; 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: 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) [45]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Regulation; 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: 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) [45]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Regulation; 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: 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) [46]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: 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) [47]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: 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: Metalloproteinase inhibitor 3 (TIMP3) [48]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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) [28]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• 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
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MDA-MB-436 cells; Breast; Homo sapiens (Human); CVCL_0623
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: 184A1 cells; Breast; Homo sapiens (Human); CVCL_3040
• In Vitro Model: HB3396 cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: 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.

Key Molecule: Estrogen receptor alpha (ESR1) [49]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: MDA-MB-157 cells; Breast; Homo sapiens (Human); CVCL_0618
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: MDA-MB-435s cells; Breast; Homo sapiens (Human); CVCL_0622
• Experiment for Molecule Alteration: Western blotting 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.

Ovarian cancer [ICD-11: 2C73]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-375 [3]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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.

Key Molecule: Protein LYRIC (MTDH) [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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 blotting 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.

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