BREAST CANCER ETIOLOGY--P53 GAIN OF FUNCTION MUTATIONS

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Breast cancer is frequently associated with mutations in the p53 gene. The presence of p53 mutations and overexpression of the epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA) indicate poor prognosis in breast cancer. In a significant number of breast cancers, mutations in the p53 gene are also accompanied by overexpression of EGFR and PCNA. Interestingly, the only known biochemical property of tumor-derived p53 mutants is the ability to transactivate promoters of growth-regulating genes including EGFR and PCNA. On the basis of this information the present proposal focuses on investigating the hypothesis that breast cancer-derived p53 mutants induce oncogenesis by actively deregulating expression of key growth- regulatory genes and different mutants differ in this ability. The following are the Specific Aims: (1) To determine the relationship between oncogenicity and transactivation potential of breast cancer- derived p53 mutants using human and murine mammary cells. Sixteen breast cancer-derived p53 mutants will be studied for comparison of transactivation and oncogenic properties. (2) To determine the relationship between p53, EGFR and PCNA levels in different breast cancer cell lines with p53 mutations identical to those studied in Specific Aim 1. (3) To determine the effects of disrupting the mutant p53 gene on the growth properties as well as on the levels of EGFR and PCNA of breast tumor cells. (4) To determine the mechanism(s) of transcriptional activation by p53 mutants. Understanding the molecular mechanism(s) of mutant p53-mediated promoter activation may elucidate the mechanism of mutant p53-mediated oncogenesis. These investigations should allow for expansion of breast cancer research in a new direction and should clarify the relationship between these three proteins in the prognosis of breast cancer. Knowledge of the properties of the individual p53 mutants may help oncologists decide the course of treatment for the breast cancer patients. Results from mutant p53-disruption experiments may open up future avenues to target mutant p53 in breast cancer.