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

Abstract

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 <i>PIK3R1</i> gene encoding p85α is a frequent event in breast cancer, with <i>PIK3R1</i> expression significantly reduced in breast tumors. <i>PIK3R1</i> knockdown transforms human mammary epithelial cells, and genetic ablation of <i>Pik3r1</i> accelerates a mouse model of HER2/neu-driven breast cancer. We demonstrate that partial loss of p85α increases the amount of p110α-p85 heterodimers bound to active receptors, augmenting PI3K signaling and oncogenic transformation. Pan-PI3K and p110α-selective pharmacological inhibition effectively blocks transformation driven by partial p85α loss both in vitro and in vivo. Together, our data suggest that p85α plays a tumor-suppressive role in transformation, and suggest that p110α-selective therapeutics may be effective in the treatment of breast cancer patients with <i>PIK3R1</i> loss.