title: Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth.
abstract: Alteration of the PTEN/PI3K pathway is associated with late-stage and castrate-resistant prostate cancer (CRPC). However, how PTEN loss is involved in CRPC development is not clear. Here, we show that castration-resistant growth is an intrinsic property of Pten null prostate cancer (CaP) cells, independent of cancer development stage. PTEN loss suppresses androgen-responsive gene expressions by modulating androgen receptor (AR) transcription factor activity. Conditional deletion of Ar in the epithelium promotes the proliferation of Pten null cancer cells, at least in part, by downregulating the androgen-responsive gene Fkbp5 and preventing PHLPP-mediated AKT inhibition. Our findings identify PI3K and AR pathway crosstalk as a mechanism of CRPC development, with potentially important implications for CaP etiology and therapy.
authors.affiliation: Department of Molecular and Medical Pharmacology and Institute for Molecular Medicine, School of Medicine, University of California, Los Angeles, CA 90095-1735, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mulholland
authors.forename: Linh M
authors.initials: LM
authors.lastname: Tran
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Li
authors.forename: Houjian
authors.initials: H
authors.lastname: Cai
authors.forename: Ashkan
authors.initials: A
authors.lastname: Morim
authors.forename: Shunyou
authors.initials: S
authors.lastname: Wang
authors.forename: Seema
authors.initials: S
authors.lastname: Plaisier
authors.forename: Isla P
authors.initials: IP
authors.lastname: Garraway
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D051766:Early Growth Response Protein 1 / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology; D009919:Orchiectomy; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2; D011471:Prostatic Neoplasms / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control / Q000628:therapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D011944:Receptors, Androgen / Q000502:physiology; D022021:Tacrolimus Binding Proteins / Q000502:physiology; D000099159:Tacrolimus Binding Protein 5
chemical_list: D051766:Early Growth Response Protein 1; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D010749:Phosphoprotein Phosphatases; D063151:Polycomb Repressive Complex 2; D051057:Proto-Oncogene Proteins c-akt; D016755:Proto-Oncogene Proteins c-jun; D011944:Receptors, Androgen; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C486109:Egr1 protein, mouse; C498410:Ezh2 protein, mouse; C400601:PHLPP1 protein, human; C494929:PTEN protein, human; C487757:Pten protein, mouse