Role of the p53 Tumor Suppressor Homolog, p63, in Breast Cancer
Annual summary rept. 1 May 2005-30 Apr 2006
HARVARD MEDICAL SCHOOL BOSTON MA
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p63 is a member of the p53 gene family, and shows structural and functional similarities to the p53 tumor suppressor. While p53s role in breast carcinogenesis is well established, p63s 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, p63s functions and mechanisms cannot necessarily be extrapolated from p53 paradigms. To understand the mechanisms of transcriptional regulation by p63, we completed an analysis of in vivo p63 DNA-binding sites 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. Together, our data provide a platform for studying p63 in cancer and developmental pathways.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research