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Updated: Jun 13, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear
Paul Mak1, Irwin Leav, Bryan Pursell
1Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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.
Insights
Estrogen receptor beta (ERbeta) loss promotes aggressive prostate cancer by enabling epithelial-mesenchymal transition (EMT). Restoring ERbeta may offer a therapeutic strategy for high Gleason grade tumors.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- High Gleason grade prostate carcinomas are aggressive and poorly differentiated.
- These tumors show reduced estrogen receptor beta (ERbeta) expression.
Purpose of the Study:
- To investigate the role of ERbeta and its ligand (3beta-adiol) in maintaining prostate cancer cell phenotype.
- To elucidate the mechanism by which ERbeta influences epithelial-mesenchymal transition (EMT) and its clinical relevance.
Main Methods:
- Investigated the effect of stimuli like TGF-beta and hypoxia on ERbeta expression.
- Assessed the impact of ERbeta loss on EMT.
- Analyzed the molecular mechanism involving HIF-1alpha, VEGF-A, and Snail1.
- Compared molecular markers in high versus low Gleason grade prostate cancers.
Main Results:
- ERbeta and 3beta-adiol maintain epithelial phenotype and repress mesenchymal traits in prostate cancer.
- EMT-inducing stimuli (TGF-beta, hypoxia) decrease ERbeta expression.
- Loss of ERbeta is sufficient to induce EMT.
- ERbeta destabilizes HIF-1alpha, repressing VEGF-A; VEGF-A receptor neuropilin-1 promotes Snail1 nuclear localization, driving EMT.
- High Gleason grade cancers show increased HIF-1alpha, VEGF, and nuclear Snail1 compared to low Gleason grade cancers.
Conclusions:
- ERbeta plays a critical role in suppressing EMT in prostate cancer.
- The ERbeta/HIF-1alpha/VEGF-A/Snail1 pathway is crucial for maintaining an epithelial phenotype and is dysregulated in aggressive prostate cancers.
- Targeting this pathway could be a therapeutic strategy for high Gleason grade prostate cancer.
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