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

Abstract

SUMMARY High Gleason grade prostate carcinomas are aggressive, poorly differentiated tumors that exhibit diminished estrogen receptor β (ERβ) expression. We report that a key function of ERβ and its specific ligand 5α-androstane-3β,17β-diol (3β-adiol) is to maintain an epithelial phenotype and repress mesenchymal characteristics in prostate carcinoma. Stimuli (TGF-β and hypoxia) that induce an epithelial-mesenchymal transition (EMT) diminish ERβ expression, and loss of ERβ is sufficient to promote an EMT. The mechanism involves ERβ-mediated destabilization of HIF-1α 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-1α and VEGF expression, and Snail1 nuclear localization compared to low Gleason grade cancers.

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

“…In the normal prostate, ERβ contributes to epithelial differentiation as evidenced by the observation that ERβ knockout mice exhibit altered differentiation in the ventral prostate, whereas the glands of ERα knockout mice lack these lesions and appear to be normal (12). ERβ in human prostate cancer is of substantial relevance because there is an inverse relationship between the expression of ERβ and highly invasive prostate cancer (9,14). In pursuit of a functional basis for this relationship, we demonstrated that ERβ sustains an epithelial phenotype and impedes a mesenchymal transition in prostate cancer and we identified a metabolite of dihydrotestosterone, 5α-androstane-3β,17β4-diol (3β-adiol) as the specific ERβ ligand that mediates this function (9).…”

“…Consequently, HIF-1α is stabilized upon loss of ERβ expression or function, enabling HIF-1-mediated transcription. Several HIFtarget genes, including VEGF, lysyl oxidase, and TWIST, have the ability to promote epithelial dedifferentiation (9,(18)(19)(20). A challenging problem that emerges from these findings is how a nuclear hormone receptor induces the degradation of HIF-1α (21).…”

“…We reported that ERβ has a causal role in the genesis of this phenotype because it impedes the expression and activation of hypoxia inducible factor 1 (HIF-1). More specifically, we made the seminal finding that 3β-adiol/ERβ destabilize HIF-1α by promoting its proteasomal degradation (9). Consequently, HIF-1α is stabilized upon loss of ERβ expression or function, enabling HIF-1-mediated transcription.…”

“…ERβ in human prostate cancer is of substantial relevance because there is an inverse relationship between the expression of ERβ and highly invasive prostate cancer (9,14). In pursuit of a functional basis for this relationship, we demonstrated that ERβ sustains an epithelial phenotype and impedes a mesenchymal transition in prostate cancer and we identified a metabolite of dihydrotestosterone, 5α-androstane-3β,17β4-diol (3β-adiol) as the specific ERβ ligand that mediates this function (9). This observation is in agreement with the recent findings that 3β-adiol is a natural ligand for ERβ in prostate (13,(15)(16)(17).…”

“…In the prostate, the discovery of ERβ (4, 5) has generated intense interest in the roles played by this ER in several tissues including prostate and breast epithelia (6)(7)(8)(9)(10)(11). Increasing evidence supports the hypothesis that ERβ functions to maintain epithelial differentiation in the prostate and breast (9,10,12,13). In the normal prostate, ERβ contributes to epithelial differentiation as evidenced by the observation that ERβ knockout mice exhibit altered differentiation in the ventral prostate, whereas the glands of ERα knockout mice lack these lesions and appear to be normal (12).…”