Title

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

UMMS Affiliation

Department of Cancer Biology

Date

4-14-2010

Document Type

Article

Subjects

Epithelial Cells; Estrogen Receptor beta; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mesoderm; Prostatic Neoplasms; Transcription Factors; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

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.

Rights and Permissions

Citation: Cancer Cell. 2010 Apr 13;17(4):319-32. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

20385358