| First Author | Shuman L | Year | 2023 |
| Journal | Am J Pathol | Volume | 193 |
| Issue | 12 | Pages | 2133-2143 |
| PubMed ID | 37544503 | Mgi Jnum | J:342856 |
| Mgi Id | MGI:7561015 | Doi | 10.1016/j.ajpath.2023.07.001 |
| Citation | Shuman L, et al. (2023) Urothelium-Specific Expression of Mutationally Activated Pik3ca Initiates Early Lesions of Noninvasive Bladder Cancer. Am J Pathol 193(12):2133-2143 |
| abstractText | 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/Pik3ca(H1047R) mouse model expressing one or two R26-Pik3ca(H1047R) alleles in a urothelium-specific manner was generated. Pik3ca(H1047R) 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. While at 6 months, Pik3ca(H1047R) mice developed increased urothelial thickness and nuclear atypia, progressive disease was not observed at 12 months. Immunohistochemistry showed urothelium maintained luminal differentiation characterized by high forkhead box A1 (Foxa1) and peroxisome proliferator-activated receptor gamma expression. Surprisingly, Pik3ca(H1047R) mice subjected to low-dose carcinogen exposure [N-butyl-N-(4-hydroxybutyl)nitrosamine] 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 did not exhibit significantly increased phosphatidylinositol 3-kinase/AKT pathway activity compared with wild-type PIK3CA tumors. Overall, these data suggest that Pik3ca(H1047R) can elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations. |
