title: Conditional Expression of the Androgen Receptor Increases Susceptibility of Bladder Cancer in Mice.
abstract: Bladder cancer represents a significant human tumor burden, accounting for about 7.7% and 2.4% of all cancer cases in males and females, respectively. While men have a higher risk of developing bladder cancer, women tend to present at a later stage of disease and with more aggressive tumors. Previous studies have suggested a promotional role of androgen signaling in enhancing bladder cancer development. To directly assess the role of androgens in bladder tumorigenesis, we have developed a novel transgenic mouse strain, R26hARLoxP/+:Upk3aGCE/+, in which the human AR transgene is conditionally expressed in bladder urothelium. Intriguingly, both male and female R26hARLoxP/+:Upk3aGCE/+ mice display a higher incidence of urothelial cell carcinoma (UCC) than the age and sex matched control littermates in response to the carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). We detect expression of the human AR transgene in CK5-positive and p63-positive basal cells in bladder urothelium. Further analyses of UCC tissues from R26hARLoxP/+:Upk3aGCE/+ mice showed that the majority of tumor cells are of urothelial basal cell origin. Positive immunostaining of transgenic AR protein was observed in the majority of tumor cells of the transgenic mice, providing a link between transgenic AR expression and oncogenic transformation. We observed an increase in Ki67 positive cells within the UCC lesions of transgenic AR mice. Manipulating endogenous androgen levels by castration and androgen supplementation directly affected bladder tumor development in male and female R26hARLoxP/+:Upk3aGCE/+ mice, respectively. Taken together, our data demonstrate for the first time that conditional activation of transgenic AR expression in bladder urothelium enhances carciongen-induced bladder tumor formation in mice. This new AR transgenic mouse line mimics certain features of human bladder cancer and can be used to study bladder tumorigenesis and for drug development.
authors: Department of Urology, Stanford University School of Medicine, Stanford, CA, 94305-5328, United States of America.
authors: Daniel T
authors: DT
authors: Johnson
authors: Department of Urology, Stanford University School of Medicine, Stanford, CA, 94305-5328, United States of America.
authors: Erika
authors: E
authors: Hooker
authors: Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, 94305-5328, United States of America.
authors: Richard
authors: R
authors: Luong
authors: Department of Urology, Stanford University School of Medicine, Stanford, CA, 94305-5328, United States of America.
authors: Eun-Jeong
authors: EJ
authors: Yu
authors: Department of Urology, Stanford University School of Medicine, Stanford, CA, 94305-5328, United States of America.
authors: Yongfeng
authors: Y
authors: He
authors: Department of Urology, University of Miami Miller School of Medicine, Miami, FL, 33136, United States of America.
authors: Mark L
authors: ML
authors: Gonzalgo
authors: Department of Urology, Stanford University School of Medicine, Stanford, CA, 94305-5328, United States of America.
authors: Zijie
authors: Z
authors: Sun
mesh_terms: D000728:Androgens; D000818:Animals; D002085:Butylhydroxybutylnitrosamine; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D004343:Drug Implants; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D019426:Integrases; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009376:Neoplasms, Hormone-Dependent / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D009919:Orchiectomy; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013739:Testosterone / Q000008:administration & dosage; D019076:Transgenes; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics; D060171:Uroplakin III / Q000096:biosynthesis / Q000235:genetics
chemical_list: C410798:AR protein, human; D000728:Androgens; D004343:Drug Implants; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; C554661:Upk3a protein, mouse; D060171:Uroplakin III; D013629:Tamoxifen; D002085:Butylhydroxybutylnitrosamine; D013739:Testosterone; C045073:Cre recombinase; D019426:Integrases