title: Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity.
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.
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Itsuhiro
authors.initials: I
authors.lastname: Takizawa
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Mitchell G
authors.initials: MG
authors.lastname: Lawrence
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Preetika
authors.initials: P
authors.lastname: Balanathan
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Rebello
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, Melbourne University, Victoria, Australia.
authors.forename: Helen B
authors.initials: HB
authors.lastname: Pearson
authors.affiliation: 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.|Department of Human Genetics, McGill University, Montréal, Canada.
authors.forename: Elika
authors.initials: E
authors.lastname: Garg
authors.affiliation: TissuPath Pathology, Melbourne, Victoria, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Pedersen
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, Melbourne University, Victoria, Australia.
authors.forename: Normand
authors.initials: N
authors.lastname: Pouliot
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Nadon
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Renea A
authors.initials: RA
authors.lastname: Taylor
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, Melbourne University, Victoria, Australia.|Department of Pathology and Department of Biochemistry and Molecular Biology, the University of Melbourne, Parkville, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Humbert
authors.affiliation: 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.
authors.forename: Ivan
authors.initials: I
authors.lastname: Topisirovic
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Luc
authors.initials: L
authors.lastname: Furic
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D055785:Gene Knockdown Techniques; D016259:Genes, myc; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D047628:Estrogen Receptor alpha; D016271:Proto-Oncogene Proteins c-myc; D051059:PTEN Phosphohydrolase; D005947:Glucose