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

Am J Pathol. 2013 May;182(5):1811-20. doi: 10.1016/j.ajpath.2013.01.018. Epub 2013 Mar 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Butylhydroxybutylnitrosamine
  • Carcinogenesis / drug effects
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology*
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Curcumin / analogs & derivatives
  • Curcumin / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Damage
  • DNA Repair / drug effects
  • Humans
  • Mice
  • Models, Biological
  • Proliferating Cell Nuclear Antigen / metabolism
  • Proteolysis / drug effects
  • Receptors, Androgen / deficiency*
  • Receptors, Androgen / metabolism
  • Survival Analysis
  • Tumor Suppressor Protein p53 / metabolism
  • Urinary Bladder Neoplasms / metabolism*
  • Urinary Bladder Neoplasms / pathology*
  • Urothelium / drug effects
  • Urothelium / pathology*

Substances

  • 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one
  • Cyclin-Dependent Kinase Inhibitor p21
  • Proliferating Cell Nuclear Antigen
  • Receptors, Androgen
  • Tumor Suppressor Protein p53
  • Butylhydroxybutylnitrosamine
  • Curcumin