ESR1

Overview

ESR1 encodes the estrogen receptor alpha (ERα), a ligand-activated nuclear transcription factor. ESR1 mutations in the ligand-binding domain are the primary mechanism of acquired resistance to aromatase inhibitors in hormone receptor-positive (HR+) breast cancer.

Alterations observed in the corpus

  • ESR1 mutations were enriched after prior systemic therapy in the MSK-CHORD 24,950-patient pan-cancer real-world cohort, confirmed as post-treatment alterations in BRCA (breast cancer) patients annotated by NLP; ESR1 was grouped with CCND1 and NF1 as an endocrine-resistance signature enriched after prior therapy PMID:39506116.
  • Activating mutations in 4 metastatic breast cancer cases linked to endocrine therapy resistance; distal ESR1 binding site hypomethylation associated with suppression of cell-adhesion genes in metastases PMID:36585450
  • ILC and IDC differentially modulate ER activity via FOXA1 vs GATA3; LumA ILC has lower total and phospho-ER than LumA IDC PMID:26451490
  • Rat tumors broadly express ER protein; Esr1 mRNA correlates with Pgr expression in CRISPR-engineered ER+ breast cancer rat models; ESR1 ligand-binding-domain mutations flagged as a future expansion of the somatic editing platform PMID:26437033
  • ESR1 expression was observed in mCRPC tumors with AR transcriptional activity but absent AR protein, suggesting ERalpha may sustain AR-pathway output as an alternative activator in AR-low phenotypes PMID:26928463
  • ER status (ER+/ER-) is the primary stratifier in a 2,433-sample breast cancer mutation landscape study; ER+ tumors have distinct mutation frequencies (e.g., PIK3CA 40.1%, GATA3 11.1%) vs ER- tumors PMID:27161491
  • Metastasis-specific driver (OR=29, p=1.2e-12) in HR+/HER2− metastatic breast cancer (BRCA); 22 mBCs with hormone-receptor-domain hotspot mutations and 9 with focal amplification (combined 19% of HR+/HER2− mBC); all 22 ESR1-mutant patients had received prior endocrine therapy, establishing ESR1 as a primary mechanism of acquired endocrine resistance PMID:28027327.
  • Recurrent hotspot mutations in BRCA and UCEC, almost exclusively in post-hormone-therapy metastases; enriched in the MSK-IMPACT metastatic cohort vs TCGA, clinically relevant for hormone-therapy management PMID:28481359
  • ESR1 target genes are hypomethylated in uterine leiomyosarcoma (ULMS) compared to somatic-tissue LMS (STLMS), supporting hormonal-axis differences between uterine and soft-tissue LMS subtypes in sarcoma PMID:29100075
  • ESR1 fusions detected in 16 samples across 5 cancer types (9 in BRCA, 8 of which luminal A/B) in the TCGA pan-cancer fusion landscape; strict mutual exclusivity with ESR1 point mutations; when ESR1 is the 5’ partner the AF1 transactivation domain is preserved, when 3’ the AF2 domain is preserved; ESR1 expression is elevated in fusion-positive samples PMID:29617662.

Cancer types (linked)

  • BRCA — ESR1 mutations enriched in patients with prior systemic (endocrine) therapy; consistent with ESR1 as the canonical aromatase-inhibitor resistance mechanism PMID:39506116.

Co-occurrence and mutual exclusivity

  • Co-enriched post-treatment with CCND1 and NF1 in BRCA in MSK-CHORD; the three genes collectively define an endocrine-resistance signature PMID:39506116.

Therapeutic relevance

  • ESR1 mutation status informs second-line endocrine therapy selection (e.g., elacestrant, fulvestrant) in HR+ breast cancer; enrichment after prior systemic therapy in MSK-CHORD is consistent with clinical practice guidelines PMID:39506116.

Open questions

  • The MSK-CHORD NLP annotation of prior treatment was used to confirm post-treatment enrichment; whether ESR1 acquisition rates differ by specific endocrine agent (aromatase inhibitors vs CDK4/6 inhibitors) was not assessed PMID:39506116.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:36585450

This page was processed by crosslinker on 2026-05-14. - PMID:26451490

This page was processed by crosslinker on 2026-05-14. - PMID:26437033

This page was processed by crosslinker on 2026-05-14. - PMID:26928463

This page was processed by wiki-cli on 2026-05-14. - PMID:27161491

This page was processed by wiki-cli on 2026-05-14. - PMID:28027327

This page was processed by wiki-cli on 2026-05-14. - PMID:28481359

This page was processed by wiki-cli on 2026-05-15. - PMID:29100075

This page was processed by wiki-cli on 2026-05-15. - PMID:29617662

This page was processed by wiki-cli on 2026-05-15.