Molecule Information

General Information of the Molecule (ID: Mol00356)
Name
Estrogen receptor alpha (ESR1) ,Homo sapiens
Synonyms
ER; ER-alpha; Estradiol receptor; Nuclear receptor subfamily 3 group A member 1; ESR; NR3A1
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Molecule Type
Protein
Gene Name
ESR1
Gene ID
2099
Location
chr6:151656691-152129619[+]
Sequence
MTMTLHTKASGMALLHQIQGNELEPLNRPQLKIPLERPLGEVYLDSSKPAVYNYPEGAAY
EFNAAAAANAQVYGQTGLPYGPGSEAAAFGSNGLGGFPPLNSVSPSPLMLLHPPPQLSPF
LQPHGQQVPYYLENEPSGYTVREAGPPAFYRPNSDNRRQGGRERLASTNDKGSMAMESAK
ETRYCAVCNDYASGYHYGVWSCEGCKAFFKRSIQGHNDYMCPATNQCTIDKNRRKSCQAC
RLRKCYEVGMMKGGIRKDRRGGRMLKHKRQRDDGEGRGEVGSAGDMRAANLWPSPLMIKR
SKKNSLALSLTADQMVSALLDAEPPILYSEYDPTRPFSEASMMGLLTNLADRELVHMINW
AKRVPGFVDLTLHDQVHLLECAWLEILMIGLVWRSMEHPGKLLFAPNLLLDRNQGKCVEG
MVEIFDMLLATSSRFRMMNLQGEEFVCLKSIILLNSGVYTFLSSTLKSLEEKDHIHRVLD
KITDTLIHLMAKAGLTLQQQHQRLAQLLLILSHIRHMSNKGMEHLYSMKCKNVVPLYDLL
LEMLDAHRLHAPTSRGGASVEETDQSHLATAGSTSSHSLQKYYITGEAEGFPATV
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Function
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3.
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Uniprot ID
ESR1_HUMAN
Ensembl ID
ENSG00000091831
HGNC ID
HGNC:3467
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Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Type(s) of Resistant Mechanism of This Molecule
  ADTT: Aberration of the Drug's Therapeutic Target
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
9 drug(s) in total
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Anastrozole
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Breast cancer [1], [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Anastrozole
 Drug Info 
Molecule Alteration Missense mutation
p.Y537S
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay; Whole-genome sequencing assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens. 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.
Disease Class: Breast cancer [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Anastrozole
 Drug Info 
Molecule Alteration Missense mutation
p.Y537N
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Disease Class: Breast cancer [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Anastrozole
 Drug Info 
Molecule Alteration Missense mutation
p.Y537C
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Disease Class: Breast cancer [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Anastrozole
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Disease Class: Breast cancer [3]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Anastrozole
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Deep sequencing assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description We report here on a novel mutation of ERalpha, in which an A to G substitution at position 1,613 resulted in substitution of aspartic acid at position 538 to glycine (D538G). The mutation was identified in liver metastases obtained from patients who developed endocrine resistance, but not in samples of primary tumors obtained prior to commencing endocrine treatment. Structural modeling indicates that D538G substitution creates a conformational change that disrupts the interaction between the receptor and either estrogen or tamoxifen, but mimics the conformation of the activated receptor. Studies in cell lines confirmed ligand-independent, constitutive activity of the mutated receptor. Taken together, these data indicate the mutation D538G as a novel mechanism conferring acquired endocrine resistance.
Exemestane
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Breast cancer [1], [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Exemestane
 Drug Info 
Molecule Alteration Missense mutation
p.Y537S
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Disease Class: Breast cancer [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Exemestane
 Drug Info 
Molecule Alteration Missense mutation
p.Y537N
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Disease Class: Breast cancer [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Exemestane
 Drug Info 
Molecule Alteration Missense mutation
p.Y537C
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Disease Class: Breast cancer [2], [3]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Exemestane
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Fulvestrant
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Breast cancer [3], [4], [5]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Fulvestrant
 Drug Info 
Molecule Alteration Missense mutation
p.Y537S
Experimental Note Identified from the Human Clinical Data
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
WHIM16 cells Breast Homo sapiens (Human) N.A.
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Whole-gexome sequencing assay
Mechanism Description The ESR1-Y537S hormone-binding-domain mutation is clearly a potent cause of aromatase-inhibitor resistance.
Disease Class: Breast cancer [1], [6]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Fulvestrant
 Drug Info 
Molecule Alteration Missense mutation
p.Y537S
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.
Disease Class: Breast cancer [7], [6]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Fulvestrant
 Drug Info 
Molecule Alteration Missense mutation
p.Y537N
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.
Disease Class: Breast cancer [2], [6]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Fulvestrant
 Drug Info 
Molecule Alteration Missense mutation
p.Y537C
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.
Disease Class: Breast cancer [6]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Fulvestrant
 Drug Info 
Molecule Alteration Missense mutation
p.L536_D538>P
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.
Disease Class: Breast cancer [5], [8]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Fulvestrant
 Drug Info 
Molecule Alteration Missense mutation
p.Y537N
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.
Disease Class: Breast cancer [5]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Fulvestrant
 Drug Info 
Molecule Alteration Missense mutation
p.Y537C
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.
Disease Class: Breast cancer [5]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Fulvestrant
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
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.
Disease Class: Breast cancer [1], [3]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Fulvestrant
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Deep sequencing assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description We report here on a novel mutation of ERalpha, in which an A to G substitution at position 1,613 resulted in substitution of aspartic acid at position 538 to glycine (D538G). The mutation was identified in liver metastases obtained from patients who developed endocrine resistance, but not in samples of primary tumors obtained prior to commencing endocrine treatment. Structural modeling indicates that D538G substitution creates a conformational change that disrupts the interaction between the receptor and either estrogen or tamoxifen, but mimics the conformation of the activated receptor. Studies in cell lines confirmed ligand-independent, constitutive activity of the mutated receptor. Taken together, these data indicate the mutation D538G as a novel mechanism conferring acquired endocrine resistance.
Disease Class: Breast cancer [1]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Fulvestrant
 Drug Info 
Molecule Alteration Missense mutation
p.L536Q
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.
Letrozole
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Breast cancer [9]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Letrozole
 Drug Info 
Molecule Alteration Missense mutation
p.Y537N
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; dPCR assay
Mechanism Description Acquired mutations in the estrogen-receptor gene ESR1 can be a marker of resistance to aromatase inhibitors in metastatic breast cancer.
Disease Class: Breast cancer [9]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Letrozole
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay; dPCR assay
Mechanism Description Acquired mutations in the estrogen-receptor gene ESR1 can be a marker of resistance to aromatase inhibitors in metastatic breast cancer.
Disease Class: Breast cancer [1], [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Letrozole
 Drug Info 
Molecule Alteration Missense mutation
p.Y537S
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Disease Class: Breast cancer [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Letrozole
 Drug Info 
Molecule Alteration Missense mutation
p.Y537N
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Disease Class: Breast cancer [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Letrozole
 Drug Info 
Molecule Alteration Missense mutation
p.Y537C
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Disease Class: Breast cancer [1]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Letrozole
 Drug Info 
Molecule Alteration Missense mutation
p.L536Q
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.
Disease Class: Breast cancer [1]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Letrozole
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
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.
MPA
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Breast cancer [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug MPA
 Drug Info 
Molecule Alteration Missense mutation
p.Y537S
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Disease Class: Breast cancer [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug MPA
 Drug Info 
Molecule Alteration Missense mutation
p.Y537N
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Disease Class: Breast cancer [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug MPA
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Paclitaxel
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Disease Class: ER positive breast cancer [10]
Resistant Disease ER positive breast cancer [ICD-11: 2C60.6]
 Disease Info 
Resistant Drug Paclitaxel
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
MCF-7R cells Breast Homo sapiens (Human) CVCL_Y493
ZR-75-1R cells Breast Homo sapiens (Human) CVCL_0588
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 Annexin V apoptosis assay; Fow cytometry analysis
Mechanism Description LncRNA H19 was identified as a powerful factor associated with paclitaxel (PTX) resistance in ERalpha-positive breast cancer cells, but not in ERalpha-negative breast cancer cells. LncRNA H19 was one of the downstream target molecules of ERalpha. Altered ERalpha expression may therefore change H19 levels to modulate the apoptosis response to chemotherapy in breast cancer cells.
Palbociclib
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Breast cancer [11]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Palbociclib
 Drug Info 
Molecule Alteration Missense mutation
p.Y537S
Experimental Note Identified from the Human Clinical Data
In Vitro Model Breast cancer tissue .
Experiment for
Molecule Alteration		 Digital PCR assay
Mechanism Description We show that clonal evolution occurs frequently during treatment, reflecting substantial sub-clonal complexity in breast cancer that has progressed after prior endocrine therapy. RB1 mutations emerged only in the palbociclib plus fulvestrant arm and in a minority of patients (6/127, 4.7%, p=0.041). New driver mutations emerged in PIK3CA (p=0.00069) and ESR1 after treatment in both arms, in particular ESR1 Y537S (p=0.0037). Evolution of driver gene mutations was uncommon in patients progressing early on palbociclib plus fulvestrant but common in patients progressing later on treatment. These findings inform future treatment strategies to address resistance to palbociclib plus fulvestrant.
Tamoxifen
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Breast cancer [6]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Missense mutation
p.L536_D538>P
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.
Disease Class: Breast cancer [5]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
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.
Disease Class: Breast cancer [1], [5], [12]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Missense mutation
p.Y537S
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.
Disease Class: Breast cancer [2], [5], [7]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Missense mutation
p.Y537N
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.
Disease Class: Breast cancer [2], [5], [13]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Missense mutation
p.Y537C
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.
Disease Class: Breast cancer [1], [3], [12]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
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.
Disease Class: Breast cancer [1]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Missense mutation
p.L536Q
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.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Breast cancer [14]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Expression
Down-regulation
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.
Disease Class: Breast cancer [15]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation ER-alpha 36 mediated nongenomic estrogen signaling pathway Activation hsa04915
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
T47D cells Breast Homo sapiens (Human) CVCL_0553
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
MDA-MB-436 cells Breast Homo sapiens (Human) CVCL_0623
MDA-MB-468 cells Breast Homo sapiens (Human) CVCL_0419
184A1 cells Breast Homo sapiens (Human) CVCL_3040
HB3396 cells Breast Homo sapiens (Human) N.A.
MEGM cells Breast Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Luciferase assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Breast cancer patients with tumors highly expressing ER-alpha36 benefit less from tamoxifen treatment. Both mRNA and protein expression of ER-alpha36 were inhibited by let-7 mimics and enhanced by let-7 inhibitors. Our results suggested a novel regulatory mechanism of let-7 miRNAs on ER-alpha36 mediated nongenomic estrogen signal pathways and Tam resistance.
Disease Class: Breast cancer [15]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Tamoxifen
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation ER-alpha 36 mediated nongenomic estrogen signaling pathway Activation hsa04915
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
T47D cells Breast Homo sapiens (Human) CVCL_0553
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
MDA-MB-436 cells Breast Homo sapiens (Human) CVCL_0623
MDA-MB-468 cells Breast Homo sapiens (Human) CVCL_0419
184A1 cells Breast Homo sapiens (Human) CVCL_3040
HB3396 cells Breast Homo sapiens (Human) N.A.
MEGM cells Breast Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Luciferase assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Breast cancer patients with tumors highly expressing ER-alpha36 benefit less from tamoxifen treatment. Both mRNA and protein expression of ER-alpha36 were inhibited by let-7 mimics and enhanced by let-7 inhibitors. Our results suggested a novel regulatory mechanism of let-7 miRNAs on ER-alpha36 mediated nongenomic estrogen signal pathways and Tam resistance.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Breast cancer [16]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Sensitive Drug Tamoxifen
 Drug Info 
Molecule Alteration Expression
Up-regulation
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
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.
Disease Class: Breast cancer [17]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Sensitive Drug Tamoxifen
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation AKT/mTOR signaling pathway Regulation hsa04150
Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
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.
Disease Class: Breast cancer [15]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Sensitive Drug Tamoxifen
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation ER-alpha 36 mediated nongenomic estrogen signaling pathway Inhibition hsa04915
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
T47D cells Breast Homo sapiens (Human) CVCL_0553
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
MDA-MB-436 cells Breast Homo sapiens (Human) CVCL_0623
MDA-MB-468 cells Breast Homo sapiens (Human) CVCL_0419
184A1 cells Breast Homo sapiens (Human) CVCL_3040
HB3396 cells Breast Homo sapiens (Human) N.A.
MEGM cells Breast Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Luciferase assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Let-7 miRNAs (b and i) enhanced tamoxifen sensitivity of tamoxifen-resistant breast cancer cells by targeting ER-alpha36 expression.
Disease Class: Breast cancer [18]
Sensitive Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Sensitive Drug Tamoxifen
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Identified from the Human Clinical Data
In Vitro Model MCF-7 cells Breast Homo sapiens (Human) CVCL_0031
SkBR3 cells Breast Homo sapiens (Human) CVCL_0033
MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
T47D cells Breast Homo sapiens (Human) CVCL_0553
BT474 cells Breast Homo sapiens (Human) CVCL_0179
MDA-MB-453 cells Breast Homo sapiens (Human) CVCL_0418
MDA-MB-468 cells Breast Homo sapiens (Human) CVCL_0419
Hs-578T cells Breast Homo sapiens (Human) CVCL_0332
MCF10A cells Breast Homo sapiens (Human) CVCL_0598
MDA-MB-157 cells Breast Homo sapiens (Human) CVCL_0618
MDA-MB-361 cells Breast Homo sapiens (Human) CVCL_0620
MDA-MB-435s cells Breast Homo sapiens (Human) CVCL_0622
Experiment for
Molecule Alteration		 Western 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.
Toremifene
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Breast cancer [2]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Toremifene
 Drug Info 
Molecule Alteration Missense mutation
p.Y537C
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Droplet digital polymerase chain reaction assay
Experiment for
Drug Resistance		 Chest x-ray assay; Computed tomography assay; Magnetic resonance imaging assay; Positron emission tomography assay
Mechanism Description We have developed a ddPCR-based method for the sensitive detection and quantification of 4 representative ESR1 mutations, Y537S, Y537N, Y537C, and D538G, in 325 breast cancer specimens, in which 270 primary breast cancer and 55 MBC specimens.
Preclinical Drug(s)
1 drug(s) in total
Click to Show/Hide the Full List of Drugs
Hormone therapy
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Breast adenocarcinoma [5]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Resistant Drug Hormone therapy
 Drug Info 
Molecule Alteration Missense mutation
p.D538G (c.1613A>G)
Experimental Note Identified from the Human Clinical Data
In Vitro Model MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
MDA-MB-361 cells Breast Homo sapiens (Human) CVCL_0620
MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
SkBR3 MCF7 cells Breast Homo sapiens (Human) N.A.
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
Ishikawa cells Endometrium Homo sapiens (Human) CVCL_2529
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
In Vivo Model Nu/Nu athymic BALB/c female mouse model Mus musculus
Experiment for
Molecule Alteration		 IMPACT assay; Western blotting analysis; Luciferase assays; Microarrays assay
Experiment for
Drug Resistance		 MSKCC assay
Disease Class: Breast adenocarcinoma [5]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Resistant Drug Hormone therapy
 Drug Info 
Molecule Alteration Missense mutation
p.L536Q (c.1607_1608delTCinsAA)
Experimental Note Identified from the Human Clinical Data
In Vitro Model MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
MDA-MB-361 cells Breast Homo sapiens (Human) CVCL_0620
MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
SkBR3 MCF7 cells Breast Homo sapiens (Human) N.A.
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
Ishikawa cells Endometrium Homo sapiens (Human) CVCL_2529
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
In Vivo Model Nu/Nu athymic BALB/c female mouse model Mus musculus
Experiment for
Molecule Alteration		 IMPACT assay; Western blotting analysis; Luciferase assays; Microarrays assay
Experiment for
Drug Resistance		 MSKCC assay
Disease Class: Breast adenocarcinoma [5]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Resistant Drug Hormone therapy
 Drug Info 
Molecule Alteration Missense mutation
p.Y537N (c.1609T>A)
Experimental Note Identified from the Human Clinical Data
In Vitro Model MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
MDA-MB-361 cells Breast Homo sapiens (Human) CVCL_0620
MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
SkBR3 MCF7 cells Breast Homo sapiens (Human) N.A.
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
Ishikawa cells Endometrium Homo sapiens (Human) CVCL_2529
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
In Vivo Model Nu/Nu athymic BALB/c female mouse model Mus musculus
Experiment for
Molecule Alteration		 IMPACT assay; Western blotting analysis; Luciferase assays; Microarrays assay
Experiment for
Drug Resistance		 MSKCC assay
Disease Class: Breast adenocarcinoma [5]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Resistant Drug Hormone therapy
 Drug Info 
Molecule Alteration Missense mutation
p.Y537S (c.1610A>C)
Experimental Note Identified from the Human Clinical Data
In Vitro Model MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
MDA-MB-361 cells Breast Homo sapiens (Human) CVCL_0620
MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
SkBR3 MCF7 cells Breast Homo sapiens (Human) N.A.
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
Ishikawa cells Endometrium Homo sapiens (Human) CVCL_2529
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
In Vivo Model Nu/Nu athymic BALB/c female mouse model Mus musculus
Experiment for
Molecule Alteration		 IMPACT assay; Western blotting analysis; Luciferase assays; Microarrays assay
Experiment for
Drug Resistance		 MSKCC assay
Disease Class: Breast adenocarcinoma [5]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Resistant Drug Hormone therapy
 Drug Info 
Molecule Alteration Missense mutation
p.Y537C (c.1610A>G)
Experimental Note Identified from the Human Clinical Data
In Vitro Model MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
MDA-MB-361 cells Breast Homo sapiens (Human) CVCL_0620
MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
SkBR3 MCF7 cells Breast Homo sapiens (Human) N.A.
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
Ishikawa cells Endometrium Homo sapiens (Human) CVCL_2529
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
In Vivo Model Nu/Nu athymic BALB/c female mouse model Mus musculus
Experiment for
Molecule Alteration		 IMPACT assay; Western blotting analysis; Luciferase assays; Microarrays assay
Experiment for
Drug Resistance		 MSKCC assay
Investigative Drug(s)
4 drug(s) in total
Click to Show/Hide the Full List of Drugs
Anastrazola/Goserelin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Breast cancer [3]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Anastrazola/Goserelin
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Deep sequencing assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description We report here on a novel mutation of ERalpha, in which an A to G substitution at position 1,613 resulted in substitution of aspartic acid at position 538 to glycine (D538G). The mutation was identified in liver metastases obtained from patients who developed endocrine resistance, but not in samples of primary tumors obtained prior to commencing endocrine treatment. Structural modeling indicates that D538G substitution creates a conformational change that disrupts the interaction between the receptor and either estrogen or tamoxifen, but mimics the conformation of the activated receptor. Studies in cell lines confirmed ligand-independent, constitutive activity of the mutated receptor. Taken together, these data indicate the mutation D538G as a novel mechanism conferring acquired endocrine resistance.
Anti-estrogens
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Breast adenocarcinoma [5]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Resistant Drug Anti-estrogens
 Drug Info 
Molecule Alteration Missense mutation
p.P535H (c.1604C>A)
Experimental Note Identified from the Human Clinical Data
In Vitro Model MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
MDA-MB-361 cells Breast Homo sapiens (Human) CVCL_0620
MDA-MB-231cells Breast Homo sapiens (Human) CVCL_0062
SkBR3 MCF7 cells Breast Homo sapiens (Human) N.A.
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
Ishikawa cells Endometrium Homo sapiens (Human) CVCL_2529
MCF Tet-On cells Pleural effusion Homo sapiens (Human) CVCL_V332
In Vivo Model Nu/Nu athymic BALB/c female mouse model Mus musculus
Experiment for
Molecule Alteration		 IMPACT assay; Western blotting analysis; Luciferase assays; Microarrays assay
Experiment for
Drug Resistance		 MSKCC assay
Disease Class: Breast adenocarcinoma [1]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Resistant Drug Anti-estrogens
 Drug Info 
Molecule Alteration Missense mutation
p.E380Q (c.1138G>C)
Experimental Note Identified from the Human Clinical Data
Disease Class: Breast adenocarcinoma [1]
Resistant Disease Breast adenocarcinoma [ICD-11: 2C60.1]
 Disease Info 
Resistant Drug Anti-estrogens
 Drug Info 
Molecule Alteration Missense mutation
p.L536X (c.1606_1608)
Experimental Note Identified from the Human Clinical Data
Exemestane/Everolimus
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Breast cancer [6]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Exemestane/Everolimus
 Drug Info 
Molecule Alteration Missense mutation
p.Y537S
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.
Disease Class: Breast cancer [6]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Exemestane/Everolimus
 Drug Info 
Molecule Alteration Missense mutation
p.L536_D538>P
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.
Disease Class: Breast cancer [6]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Exemestane/Everolimus
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
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.
Tamoxifen/Goserelin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Breast cancer [3]
Resistant Disease Breast cancer [ICD-11: 2C60.3]
 Disease Info 
Resistant Drug Tamoxifen/Goserelin
 Drug Info 
Molecule Alteration Missense mutation
p.D538G
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Deep sequencing assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description We report here on a novel mutation of ERalpha, in which an A to G substitution at position 1,613 resulted in substitution of aspartic acid at position 538 to glycine (D538G). The mutation was identified in liver metastases obtained from patients who developed endocrine resistance, but not in samples of primary tumors obtained prior to commencing endocrine treatment. Structural modeling indicates that D538G substitution creates a conformational change that disrupts the interaction between the receptor and either estrogen or tamoxifen, but mimics the conformation of the activated receptor. Studies in cell lines confirmed ligand-independent, constitutive activity of the mutated receptor. Taken together, these data indicate the mutation D538G as a novel mechanism conferring acquired endocrine resistance.
Disease- and Tissue-specific Abundances of This Molecule
ICD Disease Classification 02
Click to Show/Hide the Resistance Disease of This Class
Breast cancer [ICD-11: 2C60]
Click to Show/Hide
Differential expression of molecule in resistant diseases
The Studied Tissue Breast tissue
The Specified Disease Breast cancer
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 5.93E-18; Fold-change: 1.85E-01; Z-score: 3.67E-01
The Expression Level of Disease Section Compare with the Adjacent Tissue p-value: 7.59E-09; Fold-change: 3.83E-01; Z-score: 7.27E-01
Molecule expression in the normal tissue adjacent to the diseased tissue of patients
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
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Download Molecule expression data of patients in the normal section of the tissue adjacent to the disease section
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Download Molecule expression data in the tissue of healthy individual
Tissue-specific Molecule Abundances in Healthy Individuals
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References
Ref 1 Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013 Dec;45(12):1446-51. doi: 10.1038/ng.2823. Epub 2013 Nov 3.
Ref 2 Droplet digital polymerase chain reaction assay for screening of ESR1 mutations in 325 breast cancer specimens. Transl Res. 2015 Dec;166(6):540-553.e2. doi: 10.1016/j.trsl.2015.09.003. Epub 2015 Sep 14.
Ref 3 D538G mutation in estrogen receptor-Alpha: A novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 2013 Dec 1;73(23):6856-64. doi: 10.1158/0008-5472.CAN-13-1197. Epub 2013 Nov 11.
Ref 4 Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep. 2013 Sep 26;4(6):1116-30. doi: 10.1016/j.celrep.2013.08.022. Epub 2013 Sep 19.
Ref 5 ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013 Dec;45(12):1439-45. doi: 10.1038/ng.2822. Epub 2013 Nov 3.
Ref 6 Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast cancer patients. Onco Targets Ther. 2015 Nov 11;8:3323-8. doi: 10.2147/OTT.S92443. eCollection 2015.
Ref 7 Emergence of constitutively active estrogen receptor-Alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014 Apr 1;20(7):1757-1767. doi: 10.1158/1078-0432.CCR-13-2332. Epub 2014 Jan 7.
Ref 8 Metastatic Breast Cancer With ESR1 Mutation: Clinical Management Considerations From the Molecular and Precision Medicine (MAP) Tumor Board at Massachusetts General Hospital. Oncologist. 2016 Sep;21(9):1035-40. doi: 10.1634/theoncologist.2016-0240. Epub 2016 Aug 22.
Ref 9 Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer. Int J Cancer. 2015 Nov 15;137(10):2513-9. doi: 10.1002/ijc.29612. Epub 2015 Jun 11.
Ref 10 LncRNA H19 confers chemoresistance in ERAlpha-positive breast cancer through epigenetic silencing of the pro-apoptotic gene BIK. Oncotarget. 2016 Dec 6;7(49):81452-81462. doi: 10.18632/oncotarget.13263.
Ref 11 The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial .Cancer Discov. 2018 Nov;8(11):1390-1403. doi: 10.1158/2159-8290.CD-18-0264. Epub 2018 Sep 11. 10.1158/2159-8290.CD-18-0264
Ref 12 Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in estrogen receptor-positive metastatic breast cancer. Clin Chem. 2015 Jul;61(7):974-82. doi: 10.1373/clinchem.2015.238717. Epub 2015 May 15.
Ref 13 The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. Nat Genet. 2016 Aug;48(8):848-55. doi: 10.1038/ng.3602. Epub 2016 Jun 27.
Ref 14 MicroRNA-335-5p and -3p synergize to inhibit estrogen receptor alpha expression and promote tamoxifen resistance. FEBS Lett. 2017 Jan;591(2):382-392. doi: 10.1002/1873-3468.12538. Epub 2017 Jan 12.
Ref 15 let-7 microRNAs induce tamoxifen sensitivity by downregulation of estrogen receptor Alpha signaling in breast cancer. Mol Med. 2011;17(11-12):1233-41. doi: 10.2119/molmed.2010.00225. Epub 2011 Jul 27.
Ref 16 MiRNA-27a sensitizes breast cancer cells to treatment with Selective Estrogen Receptor Modulators. Breast. 2019 Feb;43:31-38. doi: 10.1016/j.breast.2018.10.007. Epub 2018 Oct 18.
Ref 17 Over-expression of miR-451a can enhance the sensitivity of breast cancer cells to tamoxifen by regulating 14-3-3 Zeta, estrogen receptor Alpha, and autophagy. Life Sci. 2016 Mar 15;149:104-13. doi: 10.1016/j.lfs.2016.02.059. Epub 2016 Feb 17.
Ref 18 MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem. 2008 Nov 7;283(45):31079-86. doi: 10.1074/jbc.M806041200. Epub 2008 Sep 12.

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