Activating ESR1 Mutations in Hormone-Resistant Metastatic Breast Cancer

Nat Genet. 2013 Dec;45(12):1446-51. doi: 10.1038/ng.2823. Epub 2013 Nov 3.

Abstract

Breast cancer is the most prevalent cancer in women, and over two-thirds of cases express estrogen receptor-α (ER-α, encoded by ESR1). Through a prospective clinical sequencing program for advanced cancers, we enrolled 11 patients with ER-positive metastatic breast cancer. Whole-exome and transcriptome analysis showed that six cases harbored mutations of ESR1 affecting its ligand-binding domain (LBD), all of whom had been treated with anti-estrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas (TCGA) identified four endometrial cancers with similar mutations of ESR1. The five new LBD-localized ESR1 mutations identified here (encoding p.Leu536Gln, p.Tyr537Ser, p.Tyr537Cys, p.Tyr537Asn and p.Asp538Gly) were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro. Taken together, these studies suggest that activating mutations in ESR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology*
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm / genetics*
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Humans
  • Middle Aged
  • Mutation
  • Neoplasm Metastasis
  • Protein Interaction Domains and Motifs / genetics

Substances

  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor alpha
  • estrogen receptor alpha, human