MP98-12 FOXA1 KNOCKOUT IS ASSOCIATED WITH INCREASED CARCINOGENIC SUSCEPTIBILITY AND ANDROGEN RECEPTOR EXPRESSION IN MURINE BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology V1 Apr 2017MP98-12 FOXA1 KNOCKOUT IS ASSOCIATED WITH INCREASED CARCINOGENIC SUSCEPTIBILITY AND ANDROGEN RECEPTOR EXPRESSION IN MURINE BLADDER CANCER Lauren Shuman, Zongyu Zheng, Hironobu Yamashita, Joshua Warrick, Klaus Kaestner, and David DeGraff Lauren ShumanLauren Shuman More articles by this author , Zongyu ZhengZongyu Zheng More articles by this author , Hironobu YamashitaHironobu Yamashita More articles by this author , Joshua WarrickJoshua Warrick More articles by this author , Klaus KaestnerKlaus Kaestner More articles by this author , and David DeGraffDavid DeGraff More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3077AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES 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. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1316 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Lauren Shuman More articles by this author Zongyu Zheng More articles by this author Hironobu Yamashita More articles by this author Joshua Warrick More articles by this author Klaus Kaestner More articles by this author David DeGraff More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...