title: ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading.
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.
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Mak
authors.forename: Irwin
authors.initials: I
authors.lastname: Leav
authors.forename: Bryan
authors.initials: B
authors.lastname: Pursell
authors.forename: Donggoo
authors.initials: D
authors.lastname: Bae
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Yang
authors.forename: Cherie A
authors.initials: CA
authors.lastname: Taglienti
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Gouvin
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Sharma
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Mercurio
mesh_terms: 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*
chemical_list: 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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