P53, p63 and p73 Network in Breast Cancers

Abstract

Inactivation of the tumor suppressor p53 is the single most common genetic defect in all human cancers. The p53 tumor suppressor is critically important in regulation of cell cycle progression, senescence, differentiation, DNA repair and apoptosis. The discovery of two closely related homologues, p63 and p73, in 1997 generated instant excitement and quick expectations about their tumor suppressor functions. However, despite a remarkable structural and partial functional similarity among p53, initial p63 and p73 mouse knockout studies revealed an unexpected functional diversity among them. p63 and p73 knockouts exhibit severe developmental abnormalities but no increased cancer susceptibility. While p53 is frequently mutated during tumorigenesis (in over 50% of human tumors), p63 and p73 are rarely mutated. Instead, the p63 locus is amplified in squamous cell carcinomas (Bjorkqvist et al., 1998; Massion et al., 2003) and p73 is overexpressed in many tumor types including breast cancers (Moll and Slade, 2004; Zaika and El-Rifai, 2006; Zaika et al., 1999). Although p63 and p73 can activate apoptosis in vitro, it is clear that they are not classic Knudson-like tumor suppressors like p53. Throughout the years, impressive number of evidences has been uncovered, suggesting that the p53-family play an important role in breast cancers. The emerging picture is that of an interconnected pathway, in which all p53-family proteins are involved in the response to oncogenic stress and physiological inputs. The p53/p63/p73 family members are capable of interacting in many ways that involve direct or indirect protein interactions, regulation of same target gene promoter and regulation of each other’s promoters. As such, fluctuations in the levels of selected p53 family members (or their isoforms) might change the relative availability of shared protein partners, as multiple p53-family proteins compete for interaction. Also, differential expression of selected interactors – linked with genetic variation – may distinguish the response of the p53 pathway to the same potentially oncogenic stimuli in diverse individuals. Despite the recent advances in understanding the unique roles of p53 family protein in breast cancers, there are many outstanding questions. What are the unique functions of the TA and ∆N isoforms of p63 and p73? How is individual p53 family member mediates gene expression regulated by the interaction with mutant p53 and other family member and their splicing variants in the cell? What are the patterns of p53 family isoform expression during normal development and tumorigenesis? What are the upstream signaling pathways that regulate individual p53 family member? What are the p53, p63 and p73 target genes? Do p53, p63 and p73 regulate distinct and/or overlapping sets of genes? Understanding the