Urothelium-Specific Expression of Mutationally Activated Pik3ca Initiates Early Lesions of Noninvasive Bladder Cancer.

Although approximately 70% of bladder cancers are noninvasive and have high recurrence rates, early-stage disease is understudied. The lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. Although mutations in PIK3CA are frequent in human bladder cancer, an in vivo model for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, a Upk2-Cre/Pik3caH1047R mouse model expressing one or two R26-Pik3caH1047R alleles in a urothelium-specific manner was generated. Pik3caH1047R functionality was confirmed by quantifying Akt phosphorylation, and mice were characterized by assessing urothelial thickness, nuclear atypia, and expression of luminal and basal markers at 6 and 12 months of age. At 6 months, Pik3caH1047R mice developed increased urothelial thickness and nuclear atypia; however, at 12 months, Pik3caH1047R mice did not exhibit progressive disease. Immunohistochemistry shows urothelium maintained luminal differentiation characterized by high Foxa1 and peroxisome proliferator-activated receptor γ expression. In addition, mice were subjected to low-dose carcinogen exposure [N-butyl-N-(4-hydroxybutyl)nitrosamine]. Surprisingly, Pik3caH1047R mice exhibited no significant differences after exposure relative to mice without exposure. Furthermore, single-sample gene set enrichment analysis of invasive human tumors showed those with mutant PIK3CA do not exhibit significantly increased phosphatidylinositol 3-kinase/AKT pathway activity compared with wild-type PIK3CA tumors. Overall, these data suggest that Pik3caH1047R can elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations. Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Citation

Lauren Shuman, Jonathan Pham, Thomas Wildermuth, Xue-Ru Wu, Vonn Walter, Joshua I Warrick, David J DeGraff. Urothelium-Specific Expression of Mutationally Activated Pik3ca Initiates Early Lesions of Noninvasive Bladder Cancer. The American journal of pathology. 2023 Aug 05

PMID: 37544503

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