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

Abstract
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.
AuthorsPaul Mak, Irwin Leav, Bryan Pursell, Donggoo Bae, Xiaofang Yang, Cherie A Taglienti, Lindsey M Gouvin, Vishva M Sharma, Arthur M Mercurio
JournalCancer cell (Cancer Cell) Vol. 17 Issue 4 Pg. 319-32 (Apr 13 2010) ISSN: 1878-3686 [Electronic] United States
PMID20385358 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2010 Elsevier Inc. All rights reserved.
Chemical References
  • 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
Topics
  • Epithelial Cells (cytology, physiology)
  • Estrogen Receptor beta (physiology, therapeutic use)
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit (physiology)
  • Male
  • Mesoderm (cytology, physiology)
  • Prostatic Neoplasms (pathology, prevention & control)
  • Snail Family Transcription Factors
  • Transcription Factors (physiology)
  • Transforming Growth Factor beta (physiology)
  • Vascular Endothelial Growth Factor A (physiology)

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