Urothelium-specific expression of mutationally activatedPik3cainitiates early lesions of non-invasive bladder cancer

Abstract

AbstractDespite the fact that ∼70% of bladder cancers are non-invasive and have high recurrence rates, early stage disease is understudied. The relative lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. While mutations inPIK3CAare frequent in human bladder cancer, anin vivomodel for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, aUpk2-Cre/Pik3caH1047Rmouse model expressing one or twoR26-Pik3caH1047Ralleles in a urothelium-specific manner was created.Pik3caH1047Rfunctionality 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,Pik3caH1047Rmice developed increased urothelial thickness and nuclear atypia, however, at 12 months,Pik3caH1047Rmice did not exhibit progressive disease. Immunohistochemistry shows urothelium maintained luminal differentiation characterized by high Foxa1 and Pparγ expression. In addition, mice were subjected to low-dose carcinogen exposure (N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN)). Surprisingly,Pik3caH1047Rmice exhibited no significant differences after exposure relative to mice without exposure. Furthermore, ssGSEA analysis of invasive human tumors showed those with mutantPIK3CAdo not exhibit significantly increased PI3K/AKT pathway activity compared to wildtypePIK3CAtumors. Overall, these data suggest thatPik3caH1047Rcan elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations.