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    Research Grants Awarded

    Combination Chemoprevention Of Mutagenesis And Related Endpoints In Mammary Epithelial Cells And Rat Mammary Tissue

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    The annual breast cancer incidence in the US is about 200,000 and prevention would be of enormous value. There are a large number of purported preventive agents on the market, but no means to evaluate which are most effective. The goals of the proposed research are to determine which of a number of popular agents are likely to be most effective in preventing the initiation of breast cancer, and to combine the most promising of these into chemopreventive mixtures. The ultimate endpoint of the proposed research is the inhibition of dimethylbenzanthracene (DMBA)-induced mutagenesis in rat mammary tissue; and we hypothesize that by using a mechanism based approach to chemoprevention we can significantly inhibit mutagenesis in mammary cells in vitro and in mammary tissue in rats, using safe levels of inhibitors. Mutagenesis in whole animals represents a highly relevant surrogate for the initiation of carcinogenesis. Since mutagenesis represents one rate-limiting step in carcinogenesis, inhibition of initiation should translate into a corresponding inhibition of risk for carcinogenesis. A rational approach to discovering inhibitors of breast cancer would be to determine their effects on some of the important pathways and/or genes involved in breast carcinogenesis; and this in turn implies knowledge of mechanisms. The key pathways/genes investigated will be 1) phase 1 metabolism, 2) phase II metabolism, 3) DNA repair, 4) DNA adducts, 5) cell proliferation, and 6) lipid peroxidation. The proposed inhibitors are: resveratrol, green tea, N-acetylcysteine, lipoic acid, an antioxidant vitamin mix (ascorbate + tocopherols) and sulforophane. Agents that favorably (with respect to their expected effects on mutagenesis) modulate these endpoints will then be tested as inhibitors of DMBA-induced mutagenesis in rat mammary epithelial cells. Binary combinations of the most effective inhibitors will then be tested, as anti-mutagen mixtures and depending on the results of these assays, one or two ternary combinations will be employed. The individual agents chosen for the binary combinations will be those that each modulated a different set of targets/genes, thus providing a complementary approach to prevention. After several suitable binary combinations are identified, a complementary third agent will be added, to attempt further inhibition. The most effective anti-mutagenic single agents, binary, and possibly ternary combinations in the mammary cell line, will then tested for their abilities to inhibit DMBA-induced mammary mutagenesis in lacZ rats. To our knowledge this is the first study where an in vivo model for inhibition of mutagenesis in mammary tissue is being employed. The proposed research will also be the first to use combinations of inhibitors in this model. As mutations play critical roles in the initiation of carcinogenesis, the model is also a surrogate for initiation. Breast cancer burden can be reduced by treatment of current cases and by preventing future cases. This project focuses on prevention of future cases. However, many of the factors leading to the initiation of breast cancer may also contribute to recurrence, and prevention may then reduce the probability of recurrence in previously treated patients. Also, current treatments show varying degrees of effectiveness that are usually related to the genotype of the tumor, and multiple drugs may be necessary for effective treatment. Prevention is attractive because it occurs before the genetic diversity of tumors arises. All of the proposed agents in this study are being consumed by humans for various purposes and therefore safe doses have already been established. As a consequence, phase II trials of the most effective combinations of agents could begin, when results of this study are complete.

    Lay Abstract:
    The annual breast cancer incidence in the US is about 200,000 and prevention would be of enormous value. There are a large number of purported preventive agents on the market, but no means to evaluate which are most effective. The goals of the proposed research are to determine which of a number of popular agents are likely to be most effective in preventing the initiation of breast cancer, and to combine the most promising of these into chemopreventive mixtures. Our ultimate endpoint will be mutagenesis in rat breast tissue. The whole animal mutagenesis model is one of the very few whole-animal (as opposed to ?test tube models?) that can be used to compare cancer risk from different agents. We hypothesize that by using a mechanism based approach to chemoprevention we can significantly inhibit mutagenesis in mammary cells in vitro and in mammary tissue in rats, using safe levels of inhibitors. To our knowledge this is the first study where an in vivo model for inhibition of mutagenesis in mammary tissue will be employed. The proposed research will also be the first to use combinations of inhibitors in this model. In order to design the combinations of agents, the pathways by which the individual agents are active in inhibiting mutagenesis will be investigated. The effects of the inhibitors on these pathways will first be determined and these will be correlated with the effects of the inhibitors on mutagenesis in rat mammary cells in culture. These results will indicate which pathways the inhibitors affect. Finally the most effective combinations in the mammary cell model will be used to inhibit mutagenesis in breast tissue in the whole animal model. Thus, this project will contribute to the basic understanding of prevention of breast cancer and aid in the design of additional preventive mixtures. Breast cancer burden can be reduced by treatment of current cases and by preventing future cases. This project focuses on prevention of future cases. However, many of the factors leading to the initiation of breast cancer may also contribute to recurrence, and prevention may then reduce the probability of recurrence in previously treated patients. All of the proposed agents in this study are being consumed by humans for various purposes and therefore safe doses have already been established. As a consequence, phase II trials of the most effective combinations of agents could begin, when this study is complete.