Role of p53/p73 transcriptional network in breast cancer

p53 is crucial for breast cancer tumorogenesis. The purpose of this study is to analyze the role of the structural and functional p53 homolog, p73, in breast cancer. We have shown a strong link between p73 and breast cancer: i) p73 is overexpressed in 38% of breast cancers, and ii) endogenous p73 is induced and apoptotically activated by oncogenes E2F1, cMyc and E1A. Since E2F1 and cMyc deregulation are common genetic alterations in breast cancer, this provides an explanation for p73 overexpression in tumors. However, while this suggests that p73, like p53, has an anti-tumor safeguard role, we hypothesize that an important inhibitory cross-talk occurs between certain p53 and p73 products in tumors, thus potentially converting an anti- oncogenic synergism into an oncogenic antagonism. This is due to i) the ability to form mixed complexes between mutant p53 and wild type p73 (`double hit effect of p53 mutations`), and ii) in the mouse, the p73 gene makes a second type of product, the dominant negative Np73, a potent inhibitor of wild type p53 and p73. Recent data indicates that Np73 is often strongly upregulated in human breast and other cancers. Objective: to use functional and biochemical approaches to analyze whether this p53/p73 network exerts a positive or negative net effect on breast cancer growth in vivo. Relevance: Mutational p53 status in breast cancer has been an important but imperfect variable for predicting prognosis and guiding therapy. The discovery of this inhibitory p53/p73 network could have a major clinical impact ranging from its prognostic use to rational p53-targeted drug design.