title: Decreased tumorigenesis and mortality from bladder cancer in mice lacking urothelial androgen receptor.
abstract: Much fewer mice lacking androgen receptor (AR) in the entire body develop bladder cancer (BCa). However, the role of urothelial AR (Uro-AR) in BCa development remains unclear. In the present study, we generated mice that lacked only Uro-AR (Uro-AR(-/y)) to develop BCa by using the carcinogen BBN [N-butyl-N-(4-hydroxybutyl)-nitrosamine] and found that Uro-AR(-/y) mice had a lower incidence of BCa and a higher survival rate than did their wild-type (WT; Uro-AR(+/y)) littermates. In vitro assay also demonstrated that Uro-AR facilitates the neoplastic transformation of normal urothelial cells to carcinoma. IHC staining exhibited less DNA damage, with much higher expression of p53 and its downstream target protein PNCA in Uro-AR(-/y) than that found in WT urothelium, which suggests that Uro-AR may modulate bladder tumorigenesis through p53-PCNA DNA repair signaling. Indeed, Uro-AR(-/y) mice with the transgene, simian vacuolating virus 40 T (SV40T), in the urothelium (Uro-SV40T-AR(-/y)) had a similar incidence of BCa as did their WT littermates (Uro-SV40T-AR(+/y)), and p53 was inactivated by SV40T in both genotypes. Use of the AR degradation enhancer ASC-J9 led to suppression of bladder tumorigenesis, with few adverse effects in the BBN-induced BCa mouse model. Together, these results provide the first direct in vivo evidence that Uro-AR has an important role in promoting bladder tumorigenesis and BCa progression. Targeting AR with ASC-J9 may provide a novel approach to suppress BCa initiation.
authors.affiliation: George H. Whipple Lab for Cancer Research, the Departments of Pathology, Urology, and Radiation Oncology, and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jong-Wei
authors.initials: JW
authors.lastname: Hsu
authors.forename: Iawen
authors.initials: I
authors.lastname: Hsu
authors.forename: Defeng
authors.initials: D
authors.lastname: Xu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.forename: Chih-Rong
authors.initials: CR
authors.lastname: Shyr
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D002085:Butylhydroxybutylnitrosamine; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D006801:Humans; D051379:Mice; D008954:Models, Biological; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D011944:Receptors, Androgen / Q000172:deficiency* / Q000378:metabolism; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019459:Urothelium / Q000187:drug effects / Q000473:pathology*
chemical_list: D002085:Butylhydroxybutylnitrosamine; D003474:Curcumin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; C471106:ASC-J9 compound