ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading

Cancer Cell. 2010 Apr 13;17(4):319-32. doi: 10.1016/j.ccr.2010.02.030.


High Gleason grade prostate carcinomas are aggressive, poorly differentiated tumors that exhibit diminished estrogen receptor beta (ERbeta) expression. We report that a key function of ERbeta and its specific ligand 5alpha-androstane-3beta,17beta-diol (3beta-adiol) is to maintain an epithelial phenotype and repress mesenchymal characteristics in prostate carcinoma. Stimuli (TGF-beta and hypoxia) that induce an epithelial-mesenchymal transition (EMT) diminish ERbeta expression, and loss of ERbeta is sufficient to promote an EMT. The mechanism involves ERbeta-mediated destabilization of HIF-1alpha and transcriptional repression of VEGF-A. The VEGF-A receptor neuropilin-1 drives the EMT by promoting Snail1 nuclear localization. Importantly, this mechanism is manifested in high Gleason grade cancers, which exhibit significantly more HIF-1alpha and VEGF expression, and Snail1 nuclear localization compared to low Gleason grade cancers.

Publication types

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

MeSH terms

  • Epithelial Cells / cytology
  • Epithelial Cells / physiology
  • Estrogen Receptor beta / physiology
  • Estrogen Receptor beta / therapeutic use*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Male
  • Mesoderm / cytology
  • Mesoderm / physiology
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / prevention & control*
  • Snail Family Transcription Factors
  • Transcription Factors / physiology*
  • Transforming Growth Factor beta / physiology
  • Vascular Endothelial Growth Factor A / physiology*


  • Estrogen Receptor beta
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta
  • Vascular Endothelial Growth Factor A