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Updated: May 13, 2026
Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
Decreased tumorigenesis and mortality from bladder cancer in mice lacking urothelial androgen receptor
Jong-Wei Hsu1, Iawen Hsu, Defeng Xu
1George 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.
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.
Insights
Mice lacking the androgen receptor (AR) specifically in the urothelium show reduced bladder cancer (BCa) development. Targeting AR with ASC-J9 may offer a new strategy for BCa prevention.
Area of Science:
- Urology
- Oncology
- Molecular Biology
Background:
- The role of urothelial androgen receptor (Uro-AR) in bladder cancer (BCa) development is not fully understood.
- Previous studies suggest a link between systemic androgen receptor (AR) and BCa incidence.
Purpose of the Study:
- To investigate the specific role of Uro-AR in promoting BCa initiation and progression.
- To explore potential therapeutic strategies targeting Uro-AR for BCa prevention.
Main Methods:
- Generated urothelial AR-deficient (Uro-AR(-/y)) mice and wild-type (WT) littermates.
- Induced BCa using the carcinogen N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN).
- Utilized immunohistochemistry (IHC) and in vitro assays to assess BCa development, DNA damage, and signaling pathways (p53-PCNA).
- Administered AR degradation enhancer ASC-J9 to evaluate its therapeutic potential.
Main Results:
- Uro-AR(-/y) mice exhibited significantly lower BCa incidence and higher survival rates compared to WT mice.
- In vitro studies confirmed that Uro-AR promotes neoplastic transformation of urothelial cells.
- Uro-AR deficiency led to reduced DNA damage and altered p53-PCNA signaling.
- ASC-J9 treatment suppressed BCa development in the BBN-induced mouse model with minimal adverse effects.
Conclusions:
- Urothelial AR plays a crucial role in promoting bladder tumorigenesis and BCa progression.
- Targeting AR with ASC-J9 presents a promising novel therapeutic approach for BCa prevention and treatment.
