P53 Network in Ovarian Cancer

P53 (Tp53, tumor protein p53) is one of the most relevant human oncosuppressor genes. Accordingly, inactivation of p53 by direct mutation of the gene is one of the most frequent genetic lesions in human tumors. In Ovarian Carcinoma (OC), p53 is altered in 30–80% of cases. Molecular and genetic studies have further confirmed the relevance of p53 in the development and progression of OC. Several studied have attempted to establish the p53 status as a marker of clinicopathological features. However, the predictive value of p53 alterations is still ambiguous, suggesting that multiple factors contribute to define p53 function. One of these factors may be related to the recent discovery of p53 variants in OC that may modulate, or even antagonize wild-type p53 function (Hofstetter et al., 2010). Additional studies in molecular oncology have revealed alternative routes of p53 inactivation through deregulation of its negative regulators, MDM2 and MDM4. MDM family members are key regulators of p53 activity and levels, by acting as repressors of p53 transcriptional function and as a complex for the degradation of p53 protein. Their overexpression has been observed in many human tumors characterized by wild-type p53 status, supporting the model of multiple ways of p53 inactivation in tumor cells. In fact, p53 dysfunction measured as pathogenic mutations or altered copy number of MDM2 and MDM4, approaches 100% of confirmed high-grade serous carcinoma (Ahmed et al., 2010). Recent data, also from our group, have contributed to define an even higher level of complexity in the p53 network. Indeed, it has been shown that the canonical inhibitors MDM2 and MDM4 may actually exhibit a dual mode of action (Shmueli & Oren, 2007; Mancini et al., 2009a). Particularly, following DNA damage, MDM4 functions as a cooperative factor in p53 apoptosis and promotes cell death in cisplatinum-treated ovarian cancer cells. Accordingly, MDM4 levels/p53 status correlates significantly with chemosensitivity of OC (Mancini et al., 2009b). Interestingly, various studies have evidenced that the estrogen signalling pathway has a profound impact on the activity of MDM2/MDM4/p53 network (Bond & Levine, 2007) suggesting the relevance of hormonal status too in the prediction of p53 function. Overall, these data suggest that a combined signature of p53 network may be a better prognostic factor for clinicopathological properties of ovarian cancer in agreement to what it has been recently published (Kalloger et al., 2011). In this chapter, we will summarize all these data and try to compose potential scenario for novel predicting properties of p53 network in ovarian cancer.