The Impact of a Common Mdm2 SNP on the Sensitivity of Breast Cancer to Treatment
Annual rept. 7 May 2008-6 May 2009
UNIVERSITY OF MEDICINE AND DENTISTRY OF NEW JERSEY NEW BRUNSWICK
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The discovery of a single nucleotide polymorphism SNP in the mdm2 promoter uncovered a previously unknown role of this SNP in predicting early onset of breast and the possibility that this germ line variation could decrease the effectiveness of treatment. These outcomes are likely due to the increased expression of mdm2 protein in SNP309 individuals, which blunts the p53-mediated apoptotic response to DNA damage. The objective of this proposal is to test the hypothesis that SNP309 decreases the effectiveness of radiation and chemotherapy in breast cancer and that this negative impact can be overcome by targeted down-regulation of mdm2. There appears to be a trend toward excess contralateral events with the variant and enrichment of the variant in ER breast cancer recurrences. We observed that anti-estrogen agent, fulvestrant, causes a decrease in mdm2 protein half-life, leading to a reduction in mdm2 following treatment with this agent. We demonstrate that combined use of fulvestrant with chemotherapeutic drugs doxorubicin, etoposide and paclitaxel can enhance the sensitivity of breast cancer cells to these cytotoxic agents. We observed that mdm2 expression is differentially modulated by estrogen, the anti-estrogen tamoxifen, and genistein in a genotype-specific manner. The largest effects on reduction in mdm2 expression at the protein level occur in the mdm2 SNP309 cell line. We will continue to explore mechanistic studies in vitro while evaluating the clinical outcome associations of SNP309 to chemotherapy, hormonal therapy and radiation therapy.
- Medicine and Medical Research