PI3K-p110α mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85α

Mutation or loss of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is emerging as a transforming factor in cancer, but the mechanism of transformation has been controversial. Here we find that hemizygous deletion of the PIK3R1 gene encoding p85 alpha is a frequent event in breast cancer, with PIK3R1 expression significantly reduced in breast tumors. PIK3R1 knockdown transforms human mammary epithelial cells, and genetic ablation of Pik3r1 accelerates a mouse model of HER2/neu-driven breast cancer. We demonstrate that partial loss of p85 alpha increases the amount of p110 alpha-p85 heterodimers bound to active receptors, augmenting PI3K signaling and oncogenic transformation. Pan-PI3K and p110 alpha-selective pharmacological inhibition effectively blocks transformation driven by partial p85 alpha loss both in vitro and in vivo. Together, our data suggest that p85 alpha plays a tumor-suppressive role in transformation, and suggest that p110 alpha-selective therapeutics may be effective in the treatment of breast cancer patients with PIK3R1 loss.