Role of the p53 Tumor Suppressor Homolog, p63, in Breast Cancer

摘要

p63 is a member of the p53 gene family, and shows structural and functional similarities to the p53 tumor suppressor. While p53's role in breast carcinogenesis is well established, p63's involvement in this disease remains unclear. It has been shown that p63 is expressed in the myoepithelial cells of the breast, and that p63 is essential for mammary development. The main goal of this project is to investigate the potential role of p63 in breast cancer. Despite the homology to p53, p63's functions and mechanisms cannot necessarily be extrapolated from p53 paradigms. To understand the mechanisms of transcriptional regulation by p63, we analyzed p63 DNA-binding sites in vivo across the entire human genome. We provide evidence for the biological relevance of the binding sites identified, including motif discovery and evolutionary conservation. We also used RNAi strategies to analyze the consequences of p63 deficiency. By combining data from expression profiling of p63-depleted cells with the in vivo binding data, we identify a subset of genes that are directly regulated by p63. These include genes in cell proliferation, apoptosis, and various signaling pathways. A similar analysis of p73 DNA binding sites showed a striking overlap with p63 and evidence of co-occupancy by these two factors. These findings have implications for how these highly homologous transcription factors are recruited to DNA, and how they impact each other's respective biological functions.