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

Takizawa, Itsuhiro, Lawrence, Mitchell G., Balanathan, Preetika, Rebello, Richard, Pearson, Helen B. ORCID: https://orcid.org/0000-0002-3284-0843, Garg, Elika, Pedersen, John, Pouliot, Normand, Nadon, Robert, Watt, Matthew J., Taylor, Renea A., Humbert, Patrick, Topisirovic, Ivan, Larsson, Ola, Risbridger, Gail P. and Furic, Luc 2015. Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity. Oncotarget 6 (2) , pp. 604-616. 10.18632/oncotarget.2820

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Abstract

While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor α (ERα), the role of ERα in PCa cells within established tumors is largely unknown. Here we show that expression of ERα is increased in high grade human PCa. Similarly, ERα 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 ERα 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 ERα in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERα also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERα action. Finally, ERα 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 ERα orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	Impact Journals
ISSN:	1949-2553
Date of First Compliant Deposit:	25 February 2019
Date of Acceptance:	25 November 2014
Last Modified:	29 Jun 2023 08:36
URI:	https://orca.cardiff.ac.uk/id/eprint/103603

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