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However, resistance to endocrine therapy occurs in a significant proportion of patients, and hotspot missense point mutations of the ESR1 gene that codes for ER\u03b1 are one of the major underlying mechanisms for such resistance. Although recent research has provided novel insights into the functions and activities of mutant ER, effective therapeutics that can overcome this mutant ER-mediated endocrine resistance remain elusive. Using a circulating tumor cell line derived from a patient with metastatic breast cancer and harboring the ESR1 Y537S mutation, together with genetically engineered breast cancer cell lines carrying the same mutation, we identified a novel enhancer region that is preferentially occupied by Y537S mutant ER. Deletion of this enhancer region reduced cell proliferation and adhesion in vitro, decreased tumorigenicity in vivo, and enhanced sensitivity to fulvestrant specifically in cells harboring the Y537S ER mutation. We subsequently identified insulin-like growth factor\u2013binding protein 3 as a functional downstream target of this enhancer and validated its contribution to a subset of the phenotypes associated with the Y537S mutant ER.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Mutations in the ER can drive treatment resistance in advanced breast cancer. We identify a previously unrecognized DNA regulatory region that supports growth and drug resistance in tumors carrying the common Y537S mutation, revealing a new mechanism of resistance and a potential therapeutic vulnerability.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2767-9764.crc-26-0366","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:47:41Z","timestamp":1790275661000},"page":"2395-2411","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification and Validation of the ESR1 Y537S Mutant\u2013Enriched Enhancer and Its Downstream Target IGFBP3"],"prefix":"10.1158","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8576-9702","authenticated-orcid":false,"given":"Yonatan","family":"Amzaleg","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03taz7m60","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Southern 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