MP68-10 EXPRESSION OF TFAP2C IS ASSOCIATED WITH THE BASAL MOLECULAR SUBTYPE OF BLADDER CANCER AND INCREASED TUMOR AGGRESSIVENESS

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research IV1 Apr 2015MP68-10 EXPRESSION OF TFAP2C IS ASSOCIATED WITH THE BASAL MOLECULAR SUBTYPE OF BLADDER CANCER AND INCREASED TUMOR AGGRESSIVENESS Hironobu Yamashita, Zongyu Zheng, Vasty Osei Amponsa, Jay Raman, and David DeGraff Hironobu YamashitaHironobu Yamashita More articles by this author , Zongyu ZhengZongyu Zheng More articles by this author , Vasty Osei AmponsaVasty Osei Amponsa More articles by this author , Jay RamanJay Raman More articles by this author , and David DeGraffDavid DeGraff More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2472AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Expression of the transcription factor, Forkhead Box A1 (FOXA1) is absent in 40% of invasive urothelial cell carcinoma and 80% of squamous cell carcinomas of the bladder, while it is expressed in normal urothelium and non-invasive bladder cancers. Recent work indicates that bladder tumors molecularly characterized as “basal” exhibit decreased levels of FOXA1 expression and are enriched for squamous differentiation. Therefore, we endeavored to identify molecular factors regulated by FOXA1 that may also be associated with a basal molecular phenotype. METHODS Knock-down (KD) and overexpression studies followed by microarray analysis were performed to identify FOXA1-regulated genes. Western blotting analysis and PCR confirmed microarray findings. Immunohistochemistry (IHC) of a tissue microarray consisting of 300 clinical bladder cancer samples was performed to determine the expression of FOXA1-regulated genes in human bladder cancer tissue. Crystal violet growth assays and tissue recombination xenografting determined the impact of altered TFAP2 family members on bladder cancer cell proliferation and invasion. RESULTS To identify FOXA1-regulated genes associated with a basal molecular phenotype and important in bladder cancer, FOXA1 was knocked down and overexpressed in RT4 and T24 cell lines, respectively, with subsequent microarray analysis. This approach identified TFAP2C as a novel FOXA1-repressed gene. Western blotting analysis and PCR confirmed our microarray findings, and also identified additional TFAP2 family members (TFAP2A, TFAP2B, TFAP2D and TFAP2E) significantly regulated by FOXA1. IHC of a tissue microarray consisting of over 300 patients revealed that increased TFAP2C expression is inversely correlated with FOXA1 expression (p=0.007; rho= -0.13). Additionally, IHC revealed that increased TFAP2C expression is associated with expression of CK14 (p<0.001; rho=0.36), a marker of a basal phenotype in human bladder cancer. Overexpression of TFAP2C in RT4, T24 and HTB9 cell lines resulted in significant increases in cell proliferation and in vivo tumorigenicity (p<0.01). CONCLUSIONS We have identified TFAP2C as FOXA1-regulated transcription factor Furthermore, our data suggest that increased expression of TFAP2 family members may be partly responsible for the aggressive nature of the basal molecular subtype of human bladder cancer. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e861 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hironobu Yamashita More articles by this author Zongyu Zheng More articles by this author Vasty Osei Amponsa More articles by this author Jay Raman More articles by this author David DeGraff More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...