A mutant p53 gain of function in the oncogenic response to insulin

Obesity and type 2 diabetes, with associated chronic inflammation and metabolic syndrome, are important risk factors for malignancies. In particular, meta-analyses of clinical studies suggest that hyperinsulinemia is a major cancer risk factor. Increased levels of circulating insulin may promote tumor progression by activating insulin (INSR) and IGF1 (IGF1R) receptors, that are frequently overexpressed in cancer cells. Moreover, in obese patients insulin can synergize with inflammation to promote proliferation, survival, and dissemination of cancer cells. The kinase Akt/PKB is a key mediator of the proliferative and survival effects of insulin on tumor cells. In addition, Akt directly links hyperinsulinemia to inflammation through activation of NF-kB signaling. The tumor suppressor DAB2IP (Disabled homolog 2 interacting protein), also known as AIP1 (ASK1 interacting protein), binds and inhibits PI3K-p85, limiting AKT activation in response to various stimuli. DAB2IP also binds directly to Akt1, possibly contributing to its inhibition. In addition to its action on AKT, DAB2IP modulates multiple extracellular signals involved in cancer progression, thus acting as a tumor suppressor. Its expression is frequently reduced by methylation in tumors, but other molecular mechanism of DAB2IP inactivation in cancer have been identified. One of such mechanisms is interaction with mutant p53 proteins. Point mutation of p53 is a frequent event and a significant factor in cancer development and progression. Mutant p53 proteins (mutp53) are very stable, and acquire oncogenic properties (gain of function) that can increase proliferation, survival and metastatic potential of tumor cells. In this thesis, I demonstrate that mutant p53, by binding DAB2IP, promotes insulin-induced AKT activation in triple negative breast cancer and androgen-independent prostate cancer cell lines, with cell-autonomous effects on proliferation and survival. Using a decoy protein to displace the mutp53-DAB2IP interaction, I showed that formation of this cytoplasmic complex is necessary for the enhanced response to insulin observed in mutant p53-bearing cancer cells. Together, the evidences reported in this Thesis underline a specific gain of function of mutp53 in the response of cancer cells to insulin stimulation, offering an additional perspective to understand the complex relationship between hyperinsulinemia and cancer evolution.