Deguelin in therapy of triple negative breast cancer

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DESCRIPTION (provided by applicant): Treatment of breast cancer patients with antiestrogens and aromatase inhibitor(s) has been successfully used for steroid receptor positive breast cancers. More recently herceptin has become treatment of choice for patients exhibiting HER2/neu. However, breast cancer patients expressing estrogen and progesterone receptor negative status as well as are negative for HER2/neu only have a few chemotherapeutic options available. As a result, searching for appropriate therapy regimen for these triple negative breast cancers has become a major focus of investigations for many laboratories. During our program for identifying natural inhibitors of carcinogenesis, we isolated deguelin, a phytochemical present in an African plant Mundulea sericea (Leguminossae) via an activity guided fractionation based on mechanistically regulated bioassays. Deguelin induced apoptosis in many cancer cell lines, inhibited development of precancerous lesions in mammary glands in organ cultures, inhibited development of papilloma in two-stage skin carcinogenesis, suppressed tumor multiplicity in MNU-induced mammary carcinogenesis and suppressed ornithine decarboxylase activity. More recently we observed that it selectively inhibited proliferation of four cell lines characterized as triple negative breast cancer cells. Preliminary experiment evaluating microarray profile indicated differential expression of two independent pathways including clusters of apoptosis and Wnt/beta- catenin signaling genes in cells as a result of deguelin treatment. More importantly, deguelin has been considered for clinical trials for lung cancer patients. The proposed studies in this application will provide an immediate opportunity for translational application of deguelin for triple negative breast cancer patients. The overall objective is to understand role of deguelin for ER, PR and Her2/neu negative breast cancer cells in vitro and in vivo and to see if deguelin can be used as a targeted therapy for Triple Negative Breast Cancer (TNBC) patients. The specific objectives are: 1aTo evaluate the efficacy of deguelin using twelve commercially available breast cancer cell lines representing the three major classifications of breast cancers: ER and PR positive, HER-2 amplified, and Triple (ER, PR, Her2/neu) Negative. 1. To identify deguelin mediated molecular events during the development of steroid receptor positive and negative preneoplastic lesions in mouse mammary gland organ culture (MMOC). 2. To determine the effects of deguelin and its metabolism by TNBC cells in vivo using orthotopic transplantation model. 3. To delineate the target(s) of deguelin action. The results will provide an opportunity for TNBC patients to a new targeted selective therapy.