ERβ Impedes Prostate Cancer EMT by Destabilizing HIF-1α 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 (ER beta) expression. We report that a key function of ER beta and its specific ligand 5 alpha-androstane-3 beta,17 beta-diol (3 beta-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 ER beta expression, and loss of ER beta is sufficient to promote an EMT. The mechanism involves ER beta-mediated destabilization of HIF-1 alpha and transcriptional repression of VEGF-A. The VEGF-A receptor neuropilin-1 drives the EMT by promoting Snaill nuclear localization. Importantly, this mechanism is manifested in high Gleason grade cancers, which exhibit significantly more HIF-1 alpha and VEGF expression, and Snail1 nuclear localization compared to low Gleason grade cancers.