Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor

Nat Cell Biol. 2001 Jan;3(1):30-7. doi: 10.1038/35050532.

Abstract

Activation of the heregulin/HER2 pathway in oestrogen receptor (ER)-positive breast-cancer cells leads to suppression of oestrogen-receptor element (ERE)-driven transcription and disruption of oestradiol responsiveness, and thus contributes to progression of tumours to more invasive phenotypes. Here we report the identification of metastatic-associated protein 1 (MTA1), a component of histone deacetylase (HDAC) and nucleosome-remodelling complexes, as a gene product induced by heregulin-beta1 (HRG). Stimulation of cells with HRG is accompanied by suppression of histone acetylation and enhancement of deacetylase activity. MTA1 is also a potent corepressor of ERE transcription, as it blocks the ability of oestradiol to stimulate ER-mediated transcription. The histone-deacetylase inhibitor trichostatin A blocks MTA1-mediated repression of ERE transcription. Furthermore, MTA1 directly interacts with histone deacetylase-1 and -2 and with the activation domain of ER-alpha. Overexpression of MTA1 in breast-cancer cells is accompanied by enhancement of the ability of cells to invade and to grow in an anchorage-independent manner. HRG also promotes interaction of MTA1 with endogenous ER and association of MTA1 or HDAC with ERE-responsive target-gene promoters in vivo. These results identify ER-mediated transcription as a nuclear target of MTA1 and indicate that HDAC complexes associated with the MTA1 corepressor may mediate ER transcriptional repression by HRG.

Publication types

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

MeSH terms

  • Acetylation / drug effects
  • Breast / drug effects
  • Breast / embryology
  • Breast / metabolism
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / physiopathology
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology*
  • Genes, Regulator / drug effects
  • Genes, Regulator / physiology*
  • Histone Deacetylases / drug effects
  • Histone Deacetylases / metabolism
  • Histones / drug effects
  • Histones / metabolism
  • Humans
  • Neuregulin-1 / genetics*
  • Neuregulin-1 / metabolism
  • Neuregulin-1 / pharmacology
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / physiology
  • Proteins / drug effects
  • Proteins / genetics*
  • Proteins / metabolism
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / genetics*
  • Receptors, Estrogen / metabolism
  • Repressor Proteins*
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology*
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism

Substances

  • Histones
  • Mta1 protein, human
  • Neuregulin-1
  • Proteins
  • Receptors, Estrogen
  • Repressor Proteins
  • Histone Deacetylases