Estrogen Receptor [beta]2 Induces Hypoxia Signature of Gene Expression by Stabilizing HIF-1[alpha] in Prostate Cancer

• Published in: PloS one Vol. 10; no. 5
• Main Authors: Dey, Prasenjit, Velazquez-Villegas, Laura A, Faria, Michelle, Turner, Anthony, Jonsson, Philp, Webb, Paul, Williams, Cecilia, Gustafsson, Jan-Åke, Ström, Anders M
• Format: Journal Article
• Language: English
• Published: Public Library of Science 26.05.2015
• Subjects: Analysis; Cancer genetics; Care and treatment; Estrogens; Gene expression; Genetic aspects; Physiological aspects; Prostate cancer; Vascular endothelial growth factor; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128239

The estrogen receptor (ER) [beta] variant ER[beta]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[beta]2 expression in prostate cancer cells revealed that hypoxia was an overrepresented theme. Here we show that ER[beta]2 interacts with and stabilizes HIF-1[alpha] protein in normoxia, thereby inducing a hypoxic gene expression signature. HIF-1[alpha] is known to stimulate metastasis by increasing expression of Twist1 and increasing vascularization by directly activating VEGF expression. We found that ER[beta]2 interacts with HIF-1[alpha] and piggybacks to the HIF-1[alpha] response element present on the proximal Twist1 and VEGF promoters. These findings suggest that at least part of the oncogenic effects of ER[beta]2 is mediated by HIF-1[alpha] and that targeting of this ER[beta]2 - HIF-1[alpha] interaction may be a strategy to treat prostate cancer.