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.
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Authors | Paul Mak, Irwin Leav, Bryan Pursell, Donggoo Bae, Xiaofang Yang, Cherie A Taglienti, Lindsey M Gouvin, Vishva M Sharma, Arthur M Mercurio |
Journal | Cancer cell
(Cancer Cell)
Vol. 17
Issue 4
Pg. 319-32
(Apr 13 2010)
ISSN: 1878-3686 [Electronic] United States |
PMID | 20385358
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright 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
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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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