Omics analyses of a somatic <i>Trp53^R245W/+</i> breast cancer model identify cooperating driver events activating PI3K/AKT/mTOR signaling.

Abstract

Alterations of the tumor suppressor <i>TP53</i>, one of the most common events in cancer, alone are insufficient for tumor development but serve as drivers of transformation. We sought to identify cooperating events through genomic analyses of a somatic <i>Trp53^R245W</i> mouse model (equivalent to the <i>TP53^R248W</i> hot spot mutation in human cancers) that recapitulates metastatic breast-cancer development. We identified cooperating lesions similar to those found in human breast cancers. Moreover, we identified activation of the Pi3k/Akt/mTOR pathway in most tumors via mutations in <i>Pten</i>, <i>Erbb2</i>, <i>Kras</i>, and/or a recurrent <i>Pip5k1c</i> mutation that stabilizes the Pip5k1c protein and activates Pi3k/Akt/mTOR signaling. Another <i>PIP5K1C</i> family member, <i>PIP5K1A</i>, is coamplified with <i>PI4KB</i> in 18% of human breast cancer patients; both encode kinases that are responsible for production of the PI3K substrate, phosphatidylinositol 4,5-bisphosphate. Thus, the <i>TP53^R248W</i> mutation and PI3K/AKT/mTOR signaling are major cooperative events driving breast-cancer development. Additionally, a combination of two US Food and Drug Administration (FDA)-approved drugs, tigecycline and metformin, which target oxidative phosphorylation downstream of PI3K signaling, inhibited tumor cell growth and may be repurposed for breast-cancer treatment. These findings advance our understanding of how mutant p53 drives breast-tumor development and pinpoint the importance of PI3K/AKT/mTOR signaling, expanding combination therapies for breast-cancer treatment.