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Estrogen Receptor ?2 Induces Hypoxia Signature of Gene Expression by Stabilizing HIF-1? in Prostate Cancer.

ABSTRACT: The estrogen receptor (ER) ? variant ER?2 is expressed in aggressive castration-resistant prostate cancer and has been shown to correlate with decreased overall survival. Genome-wide expression analysis after ER?2 expression in prostate cancer cells revealed that hypoxia was an overrepresented theme. Here we show that ER?2 interacts with and stabilizes HIF-1? protein in normoxia, thereby inducing a hypoxic gene expression signature. HIF-1? is known to stimulate metastasis by increasing expression of Twist1 and increasing vascularization by directly activating VEGF expression. We found that ER?2 interacts with HIF-1? and piggybacks to the HIF-1? response element present on the proximal Twist1 and VEGF promoters. These findings suggest that at least part of the oncogenic effects of ER?2 is mediated by HIF-1? and that targeting of this ER?2 - HIF-1? interaction may be a strategy to treat prostate cancer.

SUBMITTER: Dey P 

PROVIDER: S-EPMC4444278 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Estrogen Receptor β2 Induces Hypoxia Signature of Gene Expression by Stabilizing HIF-1α in Prostate Cancer.

Dey Prasenjit P   Velazquez-Villegas Laura A LA   Faria Michelle M   Turner Anthony A   Jonsson Philp P   Webb Paul P   Williams Cecilia C   Gustafsson Jan-Åke JÅ   Ström Anders M AM  

PloS one 20150526 5

The estrogen receptor (ER) β variant ERβ2 is expressed in aggressive castration-resistant prostate cancer and has been shown to correlate with decreased overall survival. Genome-wide expression analysis after ERβ2 expression in prostate cancer cells revealed that hypoxia was an overrepresented theme. Here we show that ERβ2 interacts with and stabilizes HIF-1α protein in normoxia, thereby inducing a hypoxic gene expression signature. HIF-1α is known to stimulate metastasis by increasing expressio  ...[more]

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