PD37-03 EXPRESSION OF MUTANT PIK3CA IN MURINE UROTHELIAL CELLS PROVIDES A NOVEL MODEL OF EARLY STAGE BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I (PD37)1 Sep 2021PD37-03 EXPRESSION OF MUTANT PIK3CA IN MURINE UROTHELIAL CELLS PROVIDES A NOVEL MODEL OF EARLY STAGE BLADDER CANCER Lauren Shuman, Hironobu Yamashita, Thomas Wildermuth Hershey, Xue-Ru Wu, Joshua Warrick, and David DeGraff, Hershey Lauren Shuman Lauren Shuman More articles by this author , Hironobu YamashitaHironobu Yamashita More articles by this author , Thomas Wildermuth HersheyThomas Wildermuth Hershey More articles by this author , Xue-Ru WuXue-Ru Wu More articles by this author , Joshua WarrickJoshua Warrick More articles by this author , and David DeGraff, HersheyDavid DeGraff, Hershey More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002047.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite the fact that approximately 70% of newly diagnosed bladder cancers are non-invasive tumors with high rates of recurrence, non-invasive bladder cancer is significantly understudied. In part, the general lack of appropriate models to validate the contribution of specific molecular drivers in bladder tumorigenesis is a significant issue. Activating mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) are a frequent event in early stage bladder cancer, yet an in vivo model for understanding these mutations in bladder cancer is not available. METHODS: To address this gap, we have created a novel Upk2-Cre/Pik3caH1047R mouse model which expresses one or two copies of mutant Pik3caH1047R in a urothelial-specific manner. Experimental and genetic control mice were aged for 6 or 12 months, and bladders were collected for analysis. Western blotting and immunohistochemistry was used to confirm the functionality of mutant Pik3ca as well as to characterize urothelial expression differences. RESULTS: Mutant Pik3ca activity was confirmed by immunohistochemistry for phospho-Akt(Ser473). At 6 months of age, mice carrying one or two copies of mutant Pik3ca developed urothelial hyperplasia. While mice with one copy of Pik3caH1047R failed to progress to frank malignancy, activation of two copies of mutant Pik3ca resulted in the development of papillary bladder cancer at 12 months of age. Increased proliferation of bladder urothelium was confirmed by measuring urothelial thickness as well as immunohistochemistry for Ki67. Consistent with human papillary bladder cancer, immunohistochemistry also revealed high expression of luminal markers Foxa1, Pparγ, and Gata3, as well as low expression of basal markers Krt5/6 and Krt14. CONCLUSIONS: These data provide evidence of the establishment and characterization of Upk2-Cre/Pik3caH1047R mice as a novel, clinically relevant model of non-invasive bladder cancer. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e655-e656 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Lauren Shuman More articles by this author Hironobu Yamashita More articles by this author Thomas Wildermuth Hershey More articles by this author Xue-Ru Wu More articles by this author Joshua Warrick More articles by this author David DeGraff, Hershey More articles by this author Expand All Advertisement Loading ...