ESR1 (Estrogen Receptor 1): Gene, Function, and Clinical Significance
A comprehensive overview of the ESR1 gene, its protein product, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | ESR1 |
|---|---|
| Full Name | Estrogen Receptor 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 6q25.1-q25.2 |
| NCBI Gene ID | 2099 ncbi.nlm.nih.gov/gene/2099 |
| Ensembl ID | ENSG00000091831 |
| UniProt ID | P03372 |
| OMIM ID | 133430 |
| HGNC ID | 3467 |
| Aliases | ER, ESR, ESRA, Era, NR3A1, DKFZp686N23123 |
Description
The ESR1 gene encodes estrogen receptor alpha (ERα), a nuclear receptor that mediates the biological effects of estrogen. Upon ligand binding, ERα translocates to the nucleus, dimerizes, and binds to estrogen response elements (EREs) in the promoter regions of target genes, modulating their transcription. ERα also interacts with coactivators and corepressors to regulate gene expression. This receptor plays a critical role in the development and function of female reproductive tissues, bone maintenance, and cardiovascular health. Aberrant ESR1 signaling is implicated in various cancers, particularly breast and endometrial cancers, where it drives tumor growth and progression. ESR1 mutations, especially in the ligand-binding domain, are associated with resistance to endocrine therapies.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Breast Cancer | ESR1 overexpression or activating mutations (e.g., Y537S, D538G) promote ligand-independent activation, leading to tumor proliferation and endocrine resistance. | ClinVar, COSMIC, multiple studies |
| Endometrial Cancer | ESR1 alterations, including amplification and mutations, contribute to estrogen-driven tumorigenesis in the endometrium. | ClinVar, COSMIC |
| Osteoporosis | Loss-of-function ESR1 variants are associated with reduced bone mineral density and increased fracture risk due to impaired estrogen signaling in bone. | OMIM, ClinVar |
| Estrogen Resistance | Homozygous loss-of-function mutations in ESR1 cause estrogen resistance, characterized by incomplete puberty, tall stature, and osteoporosis. | OMIM, ClinVar |
| Endocrine Therapy Resistance | Acquired ESR1 mutations (e.g., in the ligand-binding domain) are frequently detected in metastatic breast cancer patients after aromatase inhibitor treatment, conferring resistance. | ClinVar, COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Breast | High (nTPM ~ 50-100) | High expression in mammary gland epithelial cells |
| Uterus | High (nTPM ~ 50-100) | High expression in endometrial and myometrial layers |
| Ovary | Moderate (nTPM ~ 20-50) | Expression in granulosa and theca cells |
| Bone | Low (nTPM < 10) | Expression in osteoblasts and osteoclasts |
| Liver | Low (nTPM < 10) | Minimal expression |
| Heart | Low (nTPM < 10) | Minimal expression |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| MCF7 | High (nTPM ~ 100) | ER-positive breast cancer cell line; widely used for ESR1 studies |
| T47D | High (nTPM ~ 80) | ER-positive breast cancer cell line |
| ZR-75-1 | High (nTPM ~ 70) | ER-positive breast cancer cell line |
| MDA-MB-231 | Low (nTPM < 5) | ER-negative breast cancer cell line; used as negative control |
| HCC1428 | Moderate (nTPM ~ 30) | ER-positive breast cancer cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Y537S | Missense (ligand-binding domain) | ~10-20% in endocrine-resistant metastatic breast cancer | Constitutive activation, ligand-independent transcription, resistance to tamoxifen and aromatase inhibitors |
| D538G | Missense (ligand-binding domain) | ~10-20% in endocrine-resistant metastatic breast cancer | Constitutive activation, ligand-independent transcription, resistance to endocrine therapy |
| E380Q | Missense (ligand-binding domain) | ~5% in endocrine-resistant breast cancer | Reduced ligand sensitivity, partial constitutive activity |
| S463P | Missense (activation function 2) | Rare | Altered coactivator binding, increased transcriptional activity |
| K303R | Missense (hinge region) | ~5% in breast cancer | Enhanced estrogen sensitivity, increased proliferation |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in ESR1 are rare and typically result in estrogen resistance, leading to impaired sexual development, osteoporosis, and metabolic abnormalities. These mutations often affect DNA binding or dimerization domains, abolishing transcriptional activity.
Gain of Function (GOF)
Gain-of-function mutations, particularly in the ligand-binding domain (e.g., Y537S, D538G), confer constitutive activation of ERα, promoting ligand-independent tumor growth and endocrine therapy resistance. These are frequently acquired during treatment.
Dominant Negative (DN)
Dominant-negative ESR1 mutations are uncommon but can occur, where the mutant receptor interferes with wild-type ERα function, reducing overall estrogen signaling. Such mutations may contribute to resistance to estrogen-dependent growth in some contexts.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity | • RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| • Estrogen response element binding | • Steroid hormone receptor activity |
| • Zinc ion binding | • Protein dimerization activity |
| • Nuclear receptor coactivator binding | • Chromatin binding |
| • Transcription coregulator binding | • Lipid binding |
Pathways
• Estrogen signaling pathway
• Progesterone-mediated oocyte maturation
• Pathways in cancer
• Breast cancer pathway
• Endocrine resistance
• Thyroid hormone signaling pathway
• HIF-1 signaling pathway
• PI3K-Akt signaling pathway
• MAPK signaling pathway
• Cell cycle regulation
Protein Summary
The ESR1 protein, estrogen receptor alpha (ERα), is a 66 kDa nuclear receptor composed of multiple functional domains: an N-terminal activation function 1 (AF1), a central DNA-binding domain (DBD) with two zinc fingers, a hinge region, and a C-terminal ligand-binding domain (LBD) that also contains activation function 2 (AF2). ERα is activated by estrogen (17β-estradiol) binding, leading to conformational changes that promote dimerization and nuclear translocation. In the nucleus, ERα binds to estrogen response elements (EREs) in target gene promoters and recruits coactivators (e.g., SRC-1, AIB1) to stimulate transcription. Alternatively, ERα can modulate gene expression via tethering to other transcription factors like AP-1 and SP-1. ERα also mediates rapid non-genomic signaling through membrane-associated receptors, activating kinase cascades (e.g., MAPK, PI3K). Post-translational modifications, including phosphorylation, acetylation, and ubiquitination, regulate ERα stability and activity. ERα is a key therapeutic target in hormone-sensitive cancers, with drugs like tamoxifen and fulvestrant acting as antagonists or degraders.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ESR1 Knockout HEK293 Cell Line | EDJ-KQ17817 | Human | 2099 | Details Get a Quote |
| Esr1 Knockout NIT-1 Cell Line | EDJ-KZ223 | Mouse | 2099 | Details Get a Quote |
| ESR1 Knockout HeLa Cell Line | EDJ-KQ53174 | Human | 2099 | Details Get a Quote |
| ESR1 Knockout A-549 Cell Line | EDJ-KQ61654 | Human | 2099 | Details Get a Quote |
| ESR1 Knockout HCT 116 Cell Line | EDJ-KQ70135 | Human | 2099 | Details Get a Quote |
| ESR1 (p.Y537N) Point Mutation in HCT 116 Cell Line | EDC03055 | Human | 2099 | Details Get a Quote |
| ESR1 (p.Y537C) Point Mutation in HCT 116 Cell Line | EDC03050 | Human | 2099 | Details Get a Quote |
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