Somatic estrogen receptor α mutations that induce dimerization promote receptor activity and breast cancer proliferation Journal Article
| Authors: | Irani, S.; Tan, W.; Li, Q.; Toy, W.; Jones, C.; Gadiya, M.; Marra, A.; Katzenellenbogen, J. A.; Carlson, K. E.; Katzenellenbogen, B. S.; Karimi, M.; Segu Rajappachetty, R.; Del Priore, I. S.; Reis-Filho, J. S.; Shen, Y.; Chandarlapaty, S. |
| Article Title: | Somatic estrogen receptor α mutations that induce dimerization promote receptor activity and breast cancer proliferation |
| 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. Copyright: © 2023, Irani et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
| Keywords: | controlled study; human cell; major clinical study; sequence analysis; somatic mutation; genetics; mutation; cancer growth; nonhuman; cell proliferation; mouse; metabolism; breast cancer; molecular dynamics; animal experiment; animal model; protein stability; in vitro study; tumor xenograft; cell assay; breast neoplasms; retrospective study; molecular cloning; genetic transfection; cell culture; breast tumor; western blotting; ligand; beta galactosidase; ligands; dimerization; conformational transition; point mutation; estradiol; nuclear localization signal; transient transfection; ligand binding; mutagenesis; complementary dna; rna extraction; short tandem repeat; estrogen receptor alpha; machine learning; sustained drug release; humans; human; female; article; cell viability assay; luciferase assay; live cell imaging; coimmunoprecipitation; mcf-7 cell line; hek293t cell line; t-47d cell line; sk-br-3 cell line; real time reverse transcription polymerase chain reaction |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 134 |
| Issue: | 1 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2024-01-02 |
| Start Page: | e163242 |
| Language: | English |
| DOI: | 10.1172/jci163242 |
| PUBMED: | 37883178 |
| PROVIDER: | scopus |
| PMCID: | PMC10760953 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK Corresponding author is Sarat Chandarlapaty -- Source: Scopus |
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278Chandarlapaty -
19Toy -
639Reis-Filho -
5Gadiya -
11LI -
44Marra -
2Jones -
1Irani
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