ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading.
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.
Mak
Paul
P
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Leav
Irwin
I
Pursell
Bryan
B
Bae
Donggoo
D
Yang
Xiaofang
X
Taglienti
Cherie A
CA
Gouvin
Lindsey M
LM
Sharma
Vishva M
VM
Mercurio
Arthur M
AM
D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D047629:Estrogen Receptor beta / Q000502:physiology / Q000627:therapeutic use*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D011471:Prostatic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D047629:Estrogen Receptor beta; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A
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