The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-alpha

Mol Endocrinol. 2007 Dec;21(12):2907-18. doi: 10.1210/me.2007-0293. Epub 2007 Aug 30.

Abstract

The estrogen receptor (ER)-alpha (ESR1) is a key regulatory molecule in mammary epithelial cell development. Loss of ER-alpha in breast cancer is correlated with poor prognosis, increased recurrence after treatment, and an elevated incidence of metastasis. A proposed molecular pathway by which ER-alpha acts to constrain invasive growth in breast cancer cells involves direct, ER-alpha-dependent expression of metastasis-associated protein 3, a cell-type-specific component of the Mi-2/NuRD chromatin remodeling complex. MTA3 in turn represses expression of Snail, a transcription factor linked to epithelial to mesenchymal transition and cancer metastasis. To elucidate its role(s) in epithelial to mesenchymal transition (EMT), we expressed Snail in the noninvasive, ER-alpha-positive MCF-7 cell line. Snail expression led to decreased cell-cell adhesion and increased cell invasiveness. Furthermore, we observed loss of ER-alpha expression at both the RNA and protein level that was accompanied by direct interaction of Snail with regulatory DNA sequences at the ESR1 locus. A consequence of loss of ER-alpha function in this system was the increased abundance of key components of the TGF-beta signaling pathway. Thus, cross-talk among ER-alpha, Snail, and the TGF-beta pathway appears to control critical phenotypic properties of breast cancer cells.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Acetylation
  • Breast Neoplasms / metabolism
  • Cell Differentiation*
  • Cell Line, Tumor
  • Down-Regulation
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Histones / metabolism
  • Humans
  • Introns / genetics
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / metabolism*
  • Microarray Analysis
  • Phenotype
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Signal Transduction
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • Estrogen Receptor alpha
  • Histones
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta
  • estrogen receptor alpha, human