Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity

Itsuhiro Takizawa, Mitchell G Lawrence, Preetika Balanathan, Richard Rebello, Helen B Pearson, Elika Garg, John S Pedersen, Normand Pouliot, Robert Nadon, Matthew J Watt, Renea A Taylor, Patrick O Humbert, Ivan Topisirovic, Ola Larsson, Gail P Risbridger, Luc Furic

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22 Citations (Scopus)

Abstract

While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor alpha (ERalpha), the role of ERalpha in PCa cells within established tumors is largely unknown. Here we show that expression of ERalpha is increased in high grade human PCa. Similarly, ERalpha is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERalpha expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERalpha in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERalpha also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERalpha action. Finally, ERalpha knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERalpha orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.
Original languageEnglish
Pages (from-to)604 - 616
Number of pages13
JournalOncotarget
Volume6
Issue number2
DOIs
Publication statusPublished - 2015

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