Cellular reprogramming by the conjoint action of ERα, FOXA1, and GATA3 to a ligand-inducible growth state

Mol Syst Biol. 2011 Aug 30;7:526. doi: 10.1038/msb.2011.59.

Abstract

Despite the role of the estrogen receptor α (ERα) pathway as a key growth driver for breast cells, the phenotypic consequence of exogenous introduction of ERα into ERα-negative cells paradoxically has been growth inhibition. We mapped the binding profiles of ERα and its interacting transcription factors (TFs), FOXA1 and GATA3 in MCF-7 breast carcinoma cells, and observed that these three TFs form a functional enhanceosome that regulates the genes driving core ERα function and cooperatively modulate the transcriptional networks previously ascribed to ERα alone. We demonstrate that these enhanceosome occupied sites are associated with optimal enhancer characteristics with highest p300 co-activator recruitment, RNA Pol II occupancy, and chromatin opening. Most importantly, we show that the transfection of all three TFs was necessary to reprogramme the ERα-negative MDA-MB-231 and BT-549 cells to restore the estrogen-responsive growth resembling estrogen-treated ERα-positive MCF-7 cells. Cumulatively, these results suggest that all the enhanceosome components comprising ERα, FOXA1, and GATA3 are necessary for the full repertoire of cancer-associated effects of the ERα.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Breast / metabolism
  • Breast / pathology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromatin Immunoprecipitation
  • Estradiol / pharmacology*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Regulatory Networks / drug effects
  • Gene Regulatory Networks / genetics*
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Hepatocyte Nuclear Factor 3-alpha / metabolism*
  • Humans
  • Ligands
  • Oligonucleotide Array Sequence Analysis
  • Plasmids
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism*
  • Transfection

Substances

  • Chromatin
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • FOXA1 protein, human
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Ligands
  • Estradiol
  • RNA Polymerase II