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    Prevention of Genome Instability in Breast Cancer by Dietary Antimutagens

    Scientific Abstract:
    Prevention of Genome Instability in Breast Cancer by Dietary Antimutagens Scientific Abstract: Breast cancer is one of the most common cancers among women in America and northwestern Europe; however, the risk of breast cancer in Asia is reduced markedly as compared to that of the West, suggesting that the discrepancy may be associated with differences in diet. Although many epidemiological studies have found a positive correlation between dietary compounds, such as caroteneoids, and a reduction of breast cancer risk, the mechanisms of such responses are unknown. In this proposal, we will investigate dietary anticarcinogens such as those found in soy (i.e. genistein), that might act as an estrogen antagonist in breast tissue by binding to the estrogen receptor (ER) and inhibiting ER-mediated gene transcription, DNA synthesis, and cancer cell growth. Lycopene, a tomato derived carotenoid, also seems effective in reducing breast cancer risk in several epidemiological studies. Since our previous studies have shown that soy and lycopene are highly effective at reducing spontaneous mutagenesis at the hprt locus of human colon carcinoma HCT116 cells, we will investigate the effects of soy products and lycopene in analogous breast cancer models. To do so, we will apply the spontaneous mutation assays optimized in our laboratory to the breast cancer cell lines BT-474 (ER+/-), MCF-7 (ER+), and MDA-MB-468 (ER-), all of which have elevated levels of spontaneous mutagenesis. We expect that both soy products, through their anti-estrogenic property, and lycopene, because of its strong antioxidant activity, will reduce the high spontaneous mutation rates of these cells. To further understand the mechanism(s) of these effects, individual hprt- mutants will be isolated and the type of mutations will be analyzed. We will also investigate whether these dietary anitmutagens are effective against environmental organochlorine pesticide (OCP)-induced genotoxicity that has been suggested to play a causative role in breast cancer. To do this we will employ non-tumorigenic human mammary epithelial (HMEC) and MCF10A cells that have intrinsically low levels of spontaneous mutation rates. Although mutations at single nucleotides is a documented form of genome instability in breast cancer cells, we will investigate other cytogenetics endpoints including microsatellites to evaluate whether such genome instability correlates with the known high rates of spontaneous mutagenesis, and to study whether genome instability at the chromosomal level can be mitigated by dietary antimutagens. These studies will further our knowledge regarding the mechanisms by which chemopreventive agents can be beneficial in the human diet to prevent or reduce the risk of breast cancer.

    Lay Abstract:
    Prevention of Genome Instability in Breast Cancer by Dietary Antimutagens Lay Abstract: Breast cancer is one of the most common cancers among women in America and northwestern Europe; however, the risk of breast cancer in Asia is markedly lower compared to that of the West. This suggests that the difference in diet may account for the reduced risk of cancer in Asian countries. This hypothesis has been supported by many epidemiological studies that have found a positive correlation between certain dietary compounds and a reduced risk for breast cancer. One of the goals of our research is to identify anticarcinogens that can be found in the diet that may prevent or reduce the risk of breast cancer. Such compounds can be found in soy products, such as genistein, and in lycopene, a compound found in tomatoes that has also been found to reduce breast cancer risk. We have previously demonstrated that lycopene and soy products are effective in reducing spontaneous mutations in colon cancer cells, therefore, we would like to investigate whether these dietary compounds can also be effective in reducing spontaneous mutations in breast cancer cells. Using cells derived from human breast cancer tumors that are grown in culture and have elevated spontaneous mutation rates, we will study whether these compounds are able to reduce the number of spontaneous mutations. Because of the anti-estrogenic activity of soy products and the antioxidant activity of lycopene, we expect that these compounds may effectively reduce spontaneous mutations. We will also investigate whether these compounds can prevent genome instability by looking at chromosomes and microsatellites in the breast tumor cells. These studies are of paramount importance because they will provide scientific support demonstrating how chemopreventive agents may be beneficial in the prevention and/or treatment of breast cancer.