Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3

Nucleic Acids Res. 2020 May 21;48(9):4756-4768. doi: 10.1093/nar/gkaa179.

Abstract

Estrogen receptors (ER) are activated by the steroid hormone 17β-estradiol. Estrogen receptor alpha (ER-α) forms a regulatory network in mammary epithelial cells and in breast cancer with the transcription factors FOXA1 and GATA3. GATA3 is one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER-α. How GATA3 mutations found in breast cancer impact genomic localization of ER-α and the transcriptional network downstream of ER-α and FOXA1 remains unclear. Here, we investigate the function of a recurrent patient-derived GATA3 mutation (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt localization of ER-α and FOXA1. Loci co-bound by all three factors are enriched for genes integral to mammary gland development as well as epithelial cell biology. This gene set is differentially regulated in GATA3 mutant cells in culture and in tumors bearing similar mutations in vivo. The altered distribution of ER-α and FOXA1 in GATA3-mutant cells is associated with altered chromatin architecture, which leads to differential gene expression. These results suggest an active role for GATA3 zinc finger 2 mutants in ER-α positive breast tumors.

Publication types

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

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Chromatin / metabolism
  • Estrogen Receptor alpha / metabolism*
  • Female
  • GATA3 Transcription Factor / genetics*
  • GATA3 Transcription Factor / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Gene Regulatory Networks*
  • Hepatocyte Nuclear Factor 3-alpha / metabolism*
  • Humans
  • Mutation
  • Transcription, Genetic

Substances

  • Chromatin
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • FOXA1 protein, human
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Hepatocyte Nuclear Factor 3-alpha