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    Awarded Grants
    Inhibition of the Breast Cancer Marker MUC1 by the Chemopreventative, Indole-3-Carbinol

    Scientific Abstract:
    Indole-3-carbinol (I3C) has been shown to be a powerful anti-cancer agent in animal models of cancer and studies are ongoing at the National Cancer Institute to test its activity as a breast cancer preventative in humans. I3C is found in cruciferous vegetables such as Brussels sprouts, cauliflower, and broccoli. It induces a G1 cell cycle arrest of breast cancer cells and also inhibits the migration and metastasis of breast cancer cells in vivo. In this proposal, we report our novel finding that I3C inhibits the expression of the breast cancer marker MUC1. MUC1 is highly overexpressed in over 90% of breast carcinomas and elevated levels of MUC1 correspond to unfavorable prognosis for breast cancer patients. Mice nullizygous for Muc1 develop slower progressing tumors and numerous studies suggest that the overexpression of MUC1 leads to a higher propensity for tumor metastasis. At the molecular level, MUC1 binds to proto-oncoproteins c-erbB2 and c-Src as well as other key proteins involved in carcinogenesis such as beta-catenin. The specific aims of this project are as follows: 1) Determine whether I3C inhibits MUC1 gene expression in several different breast cancer cell lines. 2) Characterize the molecular mechanism of MUC1 inhibition by I3C. 3) Determine whether the inhibitory effect of I3C on cancer cell proliferation and metastatic potential is attributable to its inhibition of MUC1 expression. Naturally occurring compounds and their analogues are expected to have less side effects and toxicity when used as chemopreventatives or chemotherapeutics. Improved understanding of the mechanism by which I3C inhibits carcinogenesis should lead to the development of more efficacious cancer preventatives as well as therapeutics. Furthermore, this study should provide a rational basis for the use of I3C as a treatment, either by itself or as a complementary therapy for breast cancer.

    Lay Abstract:
    Indole-3-carbinol (I3C) has been shown to be a powerful anti-cancer agent in animal models of cancer and studies are ongoing at the National Cancer Institute to test its activity as a breast cancer preventative in humans. I3C is found in vegetables such as Brussels sprouts, cauliflower, and broccoli. When breast cancer cells are treated with I3C, their growth and migration rate decreases and they have a decreased propensity for spreading, which is usually the cause of death in cancer. In this proposal, we report our novel finding that I3C lowers the expression of the breast cancer marker MUC1. MUC1 is highly overexpressed in a majority of breast carcinomas and higher levels of MUC1 correspond to unfavorable prognosis for breast cancer patients. The expression of MUC1 at high levels has been shown to accelerate cancer progression and the spreading of tumors. At the molecular level, MUC1 binds to several proteins that play pivotal roles in cancer. Therefore, any compound which lowers the expression of MUC1 should be examined further. In this application, we propose to: 1) Determine whether I3C can inhibit MUC1 expression in several different breast cancer cell lines. 2) Determine the mechanism by which I3C lowers MUC1 expression. 3) Determine whether the anticancer effects of I3C is attributable to its inhibition of MUC1 expression. Naturally occurring compounds and their analogues are expected to have less side effects and toxicity when used as chemopreventatives or chemotherapeutics. Improved understanding of the mechanism by which I3C inhibits MUC1 expression and carcinogenesis should lead to the development of improved cancer preventatives as well as therapeutics. Furthermore, it is expected that a rational basis for the use of I3C as a complementary treatment alongside conventional chemotherapies will be provided.