The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis

Class Ia phosphatidylinositol 3 kinase (PI3K) is required for oncogenic receptor-mediated transformation; however, the individual roles of the two commonly expressed class Ia PI3K isoforms in oncogenic receptor signaling have not been elucidated in vivo. Here, we show that genetic ablation of p110 alpha blocks tumor formation in both polyoma middle T antigen (MT) and HER2/Neu transgenic models of breast cancer. Surprisingly, p110 beta ablation results in both increased ductal branching and tumorigenesis. Biochemical analyses suggest a competition model in which the less active p110 beta competes with the more active p110 alpha for receptor binding sites, thereby modulating the level of PI3K activity associated with activated receptors. Our findings demonstrate a novel p110 beta-based regulatory role in receptor-mediated PI3K activity and identify p110 alpha as an important target for treatment of HER2-positive disease.