Conditional activation of Pik3caH1047R in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations

Oncogenic mutations in PIK3CA, which encodes the phosphoinositide-3-kinase (PI3K) catalytic subunit p110α, occur in ∼25% of human breast cancers. In this study, we report the development of a knock-in mouse model for breast cancer where the endogenous Pik3ca allele was modified to allow tissue-specific conditional expression of a frequently found Pik3caH1047R (Pik3cae20H1047R) mutant allele. We found that activation of the latent Pik3caH1047R allele resulted in breast tumors with multiple histological types. Whole-exome analysis of the Pik3caH1047R-driven mammary tumors identified multiple mutations, including Trp53 mutations that appeared spontaneously during the development of adenocarinoma and spindle cell tumors. Further, we used this model to test the efficacy of GDC-0941, a PI3K inhibitor, in clinical development, and showed that the tumors respond to PI3K inhibition.