Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer

The gene encoding phosphatidylinositol 3-kinase catalytic subunit a-isoform (PIK3CA, p110 alpha) is frequently activated by mutation in human cancers. Based on detection in some breast cancer precursors, PIK3CA mutations have been proposed to have a role in tumor initiation. To investigate this hypothesis, we generated a novel mouse model with a Cre-recombinase regulated allele of p110 alpha (myristoylated-p110 alpha, myr-p110 alpha) along with p53(fl/fl) deletion and Kras(G12D) also regulated by Cre-recombinase. After instillation of adenovirus-expressing Cre-recombinase into mammary ducts, we found that myr-p110 alpha accelerated breast tumor initiation in a copy number-dependent manner. Breast tumors induced by p53(fl/fl); Kras(G12D) with no or one copy of myr-p110 alpha had predominantly sarcomatoid features, whereas two copies of myr-p110 alpha resulted in tumors with a carcinoma phenotype. This novel model provides experimental support for importance of active p110 alpha in breast tumor initiation, and shows that the amount of PI3K activity can affect the rate of tumor initiation and modify the histological phenotype of breast cancer.