The p53 tumor suppressor gene is one of the most frequently mutated genes in human breast cancer and includes gain of function mutations as well as deletion mutations. Until now, it has been difficult to examine the role of p53 gene deletion in experimental mammary tumorigenesis because of the early death rate of p53 null mice due to lymphosarcomas. We have developed a p53 null mammary epithelial model by backcrossing the original p53 null mouse into Balb/c mice. Transplantation of p53 null mammary epithelial cells into the mammary fat pads of syngeneic Balb/c mice provides a unique model system to examine the effects of p53 gene deletion on a single tissue: mammary epithelial cell morphogenesis and tumorigenesis. Preliminary data demonstrate that the p53 null mammary epithelial cells are highly susceptible to tumor development and the tumors are frequently aneuploid and metastatic. In this grant application, three specific aims are proposed to examine the role of p53 gene deletion on mammary tumorigenesis.
Specific aim 1 will examine the biology of the p53-null mammary epithelial cell by determining the preneoplastic pathology, hormone interactions and hormone dependency for tumorigenesis, and the timing of aneuploidy in tumorigenesis.
Specific aim 2 will examine modified gene expression due to p53 gene deletion using cDNA arrays. Gene expression will be evaluated in nontransformed (normal) and tumor cells from both p53 wild type and null cell populations.
Specific aim 3 will analyze the functional properties of genes identified in specific aim 2 using a variety of approaches that include modulating gene expression and restoration of wild type p53 gene activity in null cells. The initial gene to be analyzed will be glutathione peroxidase which was identified as downregulated in p53 null mammary cells by cDNA array analysis. In summary, this model allows one to analyze the biological, genetic and molecular consequences of p53 gene deletion in the in situ mammary gland by taking advantage of transplantation methods.
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