ER beta Impedes Prostate Cancer EMT by Destabilizing HIF-1 alpha and Inhibiting VEGF-Mediated Snail Nuclear Localization: Implications for Gleason Grading

作者：Mak Paul; Leav Irwin; Pursell Bryan; Bae Donggoo; Yang Xiaofang; Taglienti Cherie A; Gouvin Lindsey M; Sharma Vishva M; Mercurio Arthur M^*

来源：Cancer Cell, 2010, 17(4): 319-332.

DOI：10.1016/j.ccr.2010.02.030

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.

• 出版日期2010-4-13