ArticleThe Journal of clinical investigation2024
Somatic estrogen receptor α mutations that induce dimerization promote receptor activity and breast cancer proliferation.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 22 citations in OpenAlex.
- The natural L370F ERα variant confers endocrine resistance and sensitivity to ATRA in metastatic breast cancer cells.Cell communication and signaling : CCS · 2026Article
- Pharmacotherapeutic considerations of selective estrogen receptor modulators for vascular protection.Frontiers in pharmacology · 2026Review
- CUEDC1 promotes glycolytic metabolism reprogramming through the CUEDC1/CACNG4/PI3K axis to promote ER-positive breast cancer growth.Cellular & molecular biology letters · 2025Article
- Integrated antibody language model accelerates IgG screening and design for broad-spectrum antiviral therapy.iScience · 2025Article
- Sparse networks of conformational fluctuations communicate signals within proteins.bioRxiv : the preprint server for biology · 2025Article
- eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- ESR1 testing on FFPE samples from metastatic lesions in HR + /HER2- breast cancer after progression on CDK4/6 inhibitor therapy.Breast cancer research : BCR · 2025Article
- HLA class II-restricted T cell epitopes in public neoantigens of ESR1 and PIK3CA in breast cancer.BMC cancer · 2025Article
- Heterogeneity in Cancer.Cancers · 2025Review
- Asymmetric allostery in estrogen receptor-α homodimers drives responses to the ensemble of estrogens in the hormonal milieu.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Estrogen Receptor Alpha Mutations, Truncations, Heterodimers, and Therapies.Endocrinology · 2024Review
- Correlation between the RNA Expression and the DNA Methylation of Estrogen Receptor Genes in Normal and Malignant Human Tissues.Current issues in molecular biology · 2024Article
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
Physiologic activation of estrogen receptor α (ERα) is mediated by estradiol (E2) binding in the ligand-binding pocket of the receptor, repositioning helix 12 (H12) to facilitate binding of coactivator proteins in the unoccupied coactivator binding groove. In breast cancer, activation of ERα is often observed through point mutations that lead to the same H12 repositioning in the absence of E2. Through expanded genetic sequencing of breast cancer patients, we identified a collection of mutations located far from H12 but nonetheless capable of promoting E2-independent transcription and breast cancer cell growth. Using machine learning and computational structure analyses, this set of mutants was inferred to act distinctly from the H12-repositioning mutants and instead was associated with conformational changes across the ERα dimer interface. Through both in vitro and in-cell assays of full-length ERα protein and isolated ligand-binding domain, we found that these mutants promoted ERα dimerization, stability, and nuclear localization. Point mutations that selectively disrupted dimerization abrogated E2-independent transcriptional activity of these dimer-promoting mutants. The results reveal a distinct mechanism for activation of ERα function through enforced receptor dimerization and suggest dimer disruption as a potential therapeutic strategy to treat ER-dependent cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.