ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading
Department of Cancer Biology
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
Cancer Biology | Neoplasms
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.
DOI of Published Version
Cancer Cell. 2010 Apr 13;17(4):319-32. Link to article on publisher's site
Mak P, Leav I, Pursell BM, Bae D, Yang X, Taglienti CA, Gouvin LM, Sharma VM, Mercurio AM. (2010). ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. Cancer Biology Publications. https://doi.org/10.1016/j.ccr.2010.02.030. Retrieved from https://escholarship.umassmed.edu/cancerbiology_pp/192