Deguelin in therapy of triple negative breast cancer

描述（由申请人提供）：使用抗雌激素和芳香酶抑制剂治疗乳腺癌患者已成功用于类固醇受体阳性乳腺癌。最近，赫赛汀已成为HER 2/neu患者的首选治疗药物。然而，表达雌激素和孕激素受体阴性状态以及HER 2/neu阴性的乳腺癌患者仅具有几种可用的化疗选择。因此，寻找合适的治疗方案，这些三阴性乳腺癌已成为许多实验室的主要研究重点。在我们的计划，以确定天然抑制剂的致癌作用，我们分离鱼藤素，植物化学物质存在于非洲植物Mundulea sericea（豆科）通过活性指导分馏的基础上机械调节的生物测定。鱼藤素在许多癌细胞系中诱导凋亡，在器官培养中抑制乳腺癌前病变的发展，在两阶段皮肤癌发生中抑制乳头状瘤的发展，在MNU诱导的乳腺癌发生中抑制肿瘤多样性，并抑制鸟氨酸脱羧酶活性。最近，我们观察到它选择性地抑制四种细胞系的增殖，这些细胞系的特征是三阴性乳腺癌细胞。评估微阵列谱的初步实验表明，鱼藤素处理导致细胞中两种独立途径的差异表达，包括细胞凋亡和Wnt/β-连环蛋白信号传导基因簇。更重要的是，鱼藤素已被考虑用于肺癌患者的临床试验。本申请中提出的研究将为鱼藤素在三阴性乳腺癌患者中的转化应用提供直接机会。总体目标是了解鱼藤素在体外和体内对ER、PR和Her 2/neu阴性乳腺癌细胞的作用，并观察鱼藤素是否可用作三阴性乳腺癌（TNBC）患者的靶向治疗。具体目标是：1a使用12种市售乳腺癌细胞系评估鱼藤素的功效，所述乳腺癌细胞系代表乳腺癌的三种主要分类：ER和PR阳性、HER-2扩增和三重（ER、PR、Her 2/neu）阴性。1.在小鼠乳腺器官培养物（MMOC）中，鉴定鱼藤素介导的类固醇受体阳性和阴性癌前病变发生过程中的分子事件。2.采用TNBC细胞原位移植模型，研究鱼藤素对TNBC细胞的体内作用及其代谢。3.描述鱼藤素作用的靶点。该研究结果将为TNBC患者提供一种新的靶向选择性治疗的机会。

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.