| First Author | Thorpe LM | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 27 | Pages | 7095-7100 |
| PubMed ID | 28630349 | Mgi Jnum | J:244500 |
| Mgi Id | MGI:5913279 | Doi | 10.1073/pnas.1704706114 |
| Citation | Thorpe LM, et al. (2017) PI3K-p110alpha mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85alpha. Proc Natl Acad Sci U S A 114(27):7095-7100 |
| abstractText | 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 p85alpha 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 p85alpha increases the amount of p110alpha-p85 heterodimers bound to active receptors, augmenting PI3K signaling and oncogenic transformation. Pan-PI3K and p110alpha-selective pharmacological inhibition effectively blocks transformation driven by partial p85alpha loss both in vitro and in vivo. Together, our data suggest that p85alpha plays a tumor-suppressive role in transformation, and suggest that p110alpha-selective therapeutics may be effective in the treatment of breast cancer patients with PIK3R1 loss. |
