Login to Access Video or Poster Abstract: MP98-12
Sources of Funding: R00CA17212

Introduction

In the US, men are 3 to 4 times more likely to be diagnosed with bladder cancer (BC), however, women frequently present with more advanced disease and have inferior clinical outcomes. Recent data indicates androgen (AR) and estrogen receptors (ERα and ERβ) play an important role in BC tumorigenesis and progression. These hormone receptors physically interact with transcription factor Forkhead box A1 (FOXA1), playing an important role in transcriptional activity of AR and ER. While the role for FOXA1/AR/ER complexes in BC is unknown, Foxa1 knockout (KO) results in sex-specific changes in murine urothelial differentiation. Interestingly, BC development in mice exposed to the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) also occurs in a sex-dependent manner. Therefore, we initiated a study to determine the impact of Foxa1 KO on sex-dependent development of BC in mice.

Methods

To determine the effect of Foxa1 KO on BC development in males and females, Foxa1 ablation was achieved using a tamoxifen-inducible ubiquitin Cre (UBC-CreERT2) system. Control and KO mice were then exposed to BBN for 16 weeks and bladders were harvested for H&E, immunohistochemistry (IHC), and qPCR.

Results

Following 16 weeks of BBN treatment, female control mice appeared relatively resistant to carcinogenesis compared to males, which exhibited pre-neoplastic changes including keratinizing squamous metaplasia. However, Foxa1 KO followed by BBN treatment resulted in development of keratinizing squamous metaplasia in females and progression to muscle invasive BC in males. IHC for Krt14 and Ki67 confirmed the presence of squamous differentiation and increased proliferative index in both male and female Foxa1 KO mice treated with BBN. Interestingly, our analysis also shows that nuclear AR expression is increased in male control bladder tissue compared to female control bladder tissue. However, Foxa1 KO increases AR expression independent of sex.

Conclusions

Overall, our data indicates that Foxa1 KO in adult male and female mice renders them more susceptible to carcinogen exposure. Interestingly, Foxa1 KO resulted in development of keratinizing squamous metaplasia in female mice. Additionally, AR was slightly increased in Foxa1 KO mice, independent of sex. These data indicate loss of FOXA1 in human BC may be associated with increased AR expression and activity, and subsequent disease progression. Future work includes determining ERα and ERβ expression following Foxa1 KO, as well as the mechanism by which Foxa1 KO alters AR expression and activity in BC.

Funding

R00CA17212