Portal de Periódicos da CAPES

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

2014; Impact Journals LLC; Volume: 6; Issue: 2 Linguagem: Inglês

10.18632/oncotarget.2820

1949-2553

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

Cancer, Lipids, and Metabolism

// Itsuhiro Takizawa 1,* , Mitchell G. Lawrence 1,* , Preetika Balanathan 1 , Richard Rebello 1 , Helen B. Pearson 2,3 , Elika Garg 4,5 , John Pedersen 6 , Normand Pouliot 2,3 , Robert Nadon 5 , Matthew J. Watt 7 , Renea A. Taylor 7 , Patrick Humbert 2,3,8 , Ivan Topisirovic 4 , Ola Larsson 9 , Gail P. Risbridger 1 and Luc Furic 1 1 Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia 2 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 3 Sir Peter MacCallum Department of Oncology, Melbourne University, Victoria, Australia 4 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital and Departments of Oncology, Experimental Medicine and Biochemistry, McGill University, Montréal, Canada 5 Department of Human Genetics, McGill University, Montréal, Canada 6 TissuPath Pathology, Melbourne, Victoria, Australia 7 Department of Physiology, Monash University, Clayton, Victoria, Australia 8 Department of Pathology and Department of Biochemistry and Molecular Biology, the University of Melbourne, Parkville, Australia 9 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden * These authors contributed equally to this work Correspondence: Luc Furic, email: // Gail P. Risbridger, email: // Keywords : Estrogen receptor alpha, prostate cancer, PTEN, metabolism, MYC Received : October 20, 2014 Accepted : November 25, 2014 Published : November 26, 2014 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.