Decreased tumorigenesis and mortality from bladder cancer in mice lacking urothelial androgen receptor

Jong Wei Hsu, Iawen Hsu, Defeng Xu, Hiroshi Miyamoto, Liang Liang, Xue Ru Wu, Chih Rong Shyr, Chawnshang Chang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1811-1820
Number of pages10
JournalAmerican Journal of Pathology
Volume182
Issue number5
DOIs
StatePublished - May 2013
Externally publishedYes

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Androgen Receptors
Urinary Bladder Neoplasms
Carcinogenesis
Simian virus 40
Mortality
Urothelium
Urinary Bladder
Butylhydroxybutylnitrosamine
Incidence
Proliferating Cell Nuclear Antigen
Transgenes
DNA Repair
Carcinogens
DNA Damage
Survival Rate
Genotype
Staining and Labeling
Carcinoma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Decreased tumorigenesis and mortality from bladder cancer in mice lacking urothelial androgen receptor. / Hsu, Jong Wei; Hsu, Iawen; Xu, Defeng; Miyamoto, Hiroshi; Liang, Liang; Wu, Xue Ru; Shyr, Chih Rong; Chang, Chawnshang.

In: American Journal of Pathology, Vol. 182, No. 5, 05.2013, p. 1811-1820.

Research output: Contribution to journalArticle

Hsu, JW, Hsu, I, Xu, D, Miyamoto, H, Liang, L, Wu, XR, Shyr, CR & Chang, C 2013, 'Decreased tumorigenesis and mortality from bladder cancer in mice lacking urothelial androgen receptor', American Journal of Pathology, vol. 182, no. 5, pp. 1811-1820. https://doi.org/10.1016/j.ajpath.2013.01.018
Hsu, Jong Wei ; Hsu, Iawen ; Xu, Defeng ; Miyamoto, Hiroshi ; Liang, Liang ; Wu, Xue Ru ; Shyr, Chih Rong ; Chang, Chawnshang. / Decreased tumorigenesis and mortality from bladder cancer in mice lacking urothelial androgen receptor. In: American Journal of Pathology. 2013 ; Vol. 182, No. 5. pp. 1811-1820.
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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.",
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