Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations

Cancer Cell. 2018 Feb 12;33(2):173-186.e5. doi: 10.1016/j.ccell.2018.01.004.

Abstract

Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER+) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. Analysis of the genome-wide ER binding sites identified mutant ER unique recruitment mediating the allele-specific transcriptional program. Genetic screens identified genes that are essential for the ligand-independent growth driven by the mutants. These studies provide insights into the mechanism of endocrine therapy resistance engendered by ER mutations and potential therapeutic targets.

Keywords: CDK7; breast cancer; cistrome; endocrine therapy resistance; estrogen receptor; estrogen recptor mutations.

Publication types

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

MeSH terms

  • Alleles*
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Chromatin / metabolism*
  • Drug Resistance, Neoplasm / genetics
  • Estrogen Receptor alpha / genetics*
  • Humans
  • Mice, Transgenic
  • Mutation / genetics*

Substances

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