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The Roles of p63 and p73 in the Pathogenesis of Mammary Adenocarcinoma
Tumor Cell Biology V
p53 is mutated in about 50% of human cancers and in a large proportion of mammary adenocarcinomas. Recently, two genes, p63 and p73, were discovered and found to be structurally and functionally related to p53. Since the discovery of these two genes, their roles in tumor suppression have been debated. The data regarding the status of p63 and p73 from human tumors is complex due to the fact that multiple isoforms of both genes exist and most available antibodies do not distinguish between these isoforms. Some of these isoforms lack a transactivation domain (deltaN) and are thought to act as oncogenes by negatively regulating p53 and the transactivation competent (TA) isoforms of p63 and p73. The TA isoforms are structurally and functionally much more like p53 and are thought to have tumor suppressive activities. Indeed, studies performed on human tumor samples have shown that mammary tumors lose expression of all isoforms of p63 and p73 while others overexpress deltaNp73. Little is known about the roles of these various isoforms in cancer and in mammary tumorigenesis. Using mouse models, we now have clear genetic evidence that p63 and p73 play a role in tumor suppression, metastasis, and importantly in the suppression of mammary adenocarcinomas in the mouse. In this study, we found that 20% of p63+/-;p73+/- and 10% of p53+/-;p63+/- mice develop mammary adenocarcinoma. Using gene expression and chomatin immunoprecipitation, we also have evidence that p63 and p73 regulate genes involved in mammary adenocarcinoma and DNA repair. The experiments in this proposal are designed to determine the roles of p63 and p73 in the pathogenesis of mammary adenocarcinoma, and how the distinct isoforms are acting in tumor suppression, metastasis, and chemoresistance. To address the functions of p63 and p73 in mammary adenocarcinoma, we will perform the following specific aims: (1) To develop mouse models of mammary adenocarcinoma harboring mutations in p63, p73 and its isoforms (2)To determine the mechanism of transcriptional regulation of BRCA2 and other DNA repair genes by p63 and p73. (3) To test the chemosensitivity of mammary tumors in mice mutant for p63 and/or p73. (4) To characterize the metastatic phenotype in mice deficient for p63 and p73. These experiments will allow us to understand the functions of the whole p53 family in mammary tumorigenesis and may lead to the design of more targeted therapies for patients harboring mutations in this family of genes.
p53 has long been known to be a tumor suppressor gene functioning as the “guardian of the genome” by protecting the organism from damaged cells. p53 provides protection to the organism by inducing genes that allow time to repair DNA damage or executing cells that are too damaged and harmful to the organism. Within the last ten years, two new family members of p53 were discovered and were named p63 and p73. These genes are structurally similar to p53; however, while they share some functional similarity with p53, some of their functions are different. The study of p63 and p73 is more complex than that of p53 because of the existence of multiple isoforms of p63 and p73. The full length isoforms (TA) are more structurally similar to p53 and can induce genes that protect the organism from damaged cells, while the truncated isoforms (deltaN) lack this ability and are thought to oppose the functions of p53 and the TA isoform of p63 and p73. Using mouse models, we have recently discovered that p63 and p73 have tumor suppressive functions and play a role in multiple carcinomas, including mammary adenocarcinoma, and metastasis. Mice mutant for multiple p53 family members developed very aggressive, invasive and metastatic tumors. Additional evidence from some human tumors support this finding. Tumors that are more aggressive and invasive have lost expression of p63 or p73. The goals of this proposal are to understand the genes that may be regulated by p63 and p73 in the pathogenesis of mammary adenocarcinoma. We will accomplish this by engineering mice mutant for p63, p73 and its isoforms in the mammary gland. Cells and tissues from these mice will be used to understand the regulation of genes involved in mammary adenocarcinoma by p63 and p73 and its TA isoforms. Based on prior experiments, we have data suggesting that p63 and p73 regulate BRCA2, a gene already known to play an important tumor suppressive role in breast cancer. Knowledge from the experiments in this proposal will help us gain a better understanding of how the p53 family of genes acts in tumor suppression, progression and metastasis and may help us to design more targeted therapies for cancer patients.