کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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5934308 | 1573405 | 2013 | 10 صفحه PDF | دانلود رایگان |

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-ARâ/y) to develop BCa by using the carcinogen BBN [N-butyl-N-(4-hydroxybutyl)-nitrosamine] and found that Uro-ARâ/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-ARâ/y than that found in WT urothelium, which suggests that Uro-AR may modulate bladder tumorigenesis through p53-PCNA DNA repair signaling. Indeed, Uro-ARâ/y mice with the transgene, simian vacuolating virus 40 T (SV40T), in the urothelium (Uro-SV40T-ARâ/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.
Journal: The American Journal of Pathology - Volume 182, Issue 5, May 2013, Pages 1811-1820