Deguelin in therapy of triple negative breast cancer

说明(申请人提供)：抗雌激素和芳香酶抑制剂(S)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HER2/neu患者的首选治疗方法。然而，雌激素和孕激素受体表达阴性、HER2/neu阴性的乳腺癌患者只有少数几种化疗选择。因此，为这些三阴性乳腺癌寻找合适的治疗方案已成为许多实验室的主要研究重点。在我们鉴定天然致癌抑制剂的计划中，我们通过基于机械调节的生物测定的活性引导分级分离，分离了鱼藤素，这是一种存在于非洲植物丝光植物(豆科植物)中的植物化学物质。Dguelin可诱导多种肿瘤细胞系的凋亡，抑制器官培养中乳腺癌前病变的发展，抑制二期皮肤癌中乳头状瘤的发展，抑制MNU诱导的乳腺癌发生中的肿瘤多样性，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了四种三阴性乳腺癌细胞的增殖。初步实验表明，鱼藤素处理后，细胞中存在两条独立的信号通路，包括细胞凋亡率和Wnt/β-catenin信号基因的差异表达。更重要的是，鱼藤素已被考虑用于肺癌患者的临床试验。这项申请中拟议的研究将立即为三阴性乳腺癌患者提供鱼藤素翻译应用的机会。总体目标是了解鱼藤素在体内外对ER、PR和Her2/neu阴性乳腺癌细胞的作用，并了解鱼藤素是否可用于三阴性乳腺癌(TNBC)患者的靶向治疗。具体目标是：1a使用代表三种主要类型乳腺癌的12个商业可获得的乳腺癌细胞株来评估鱼藤素的疗效：ER和PR阳性，HER-2扩增，三重(ER，PR，Her2/neu)阴性。1.鉴定鱼藤素在小鼠乳腺器官培养(MMOC)中激素受体阳性和阴性癌前病变发生过程中的分子机制。2.采用原位移植模型，研究鱼藤素在体内对TNBC细胞代谢的影响。3.勾画鱼藤素作用靶点(S)。这一结果将为TNBC患者提供一个新的靶向选择性治疗的机会。 公共卫生相关性：虽然用抗雌激素和芳香酶抑制剂(S)治疗乳腺癌患者已经成功地用于类固醇受体阳性的乳腺癌，但雌激素和孕激素受体阴性以及HER2/neu阴性的乳腺癌患者只有少数几种化疗选择。Dguelin是一种存在于非洲植物丝光植物(豆科植物)中的植物化学物质，已被证明选择性地抑制具有三重阴性乳腺癌细胞特征的MDA-MB-231细胞的增殖。由于鱼藤素已被考虑用于肺癌患者的临床试验，本申请中拟议的研究将立即为三阴性乳腺癌患者提供鱼藤素翻译应用的机会。

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. PUBLIC HEALTH RELEVANCE: Although the treatment of breast cancer patients with antiestrogens and aromatase inhibitor(s) has been successfully used for steroid receptor positive breast cancers, 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. Deguelin, a phytochemical present in an African plant Mundulea sericea (Leguminossae) has been shown to selectively inhibited proliferation of MDA-MB-231 cells characterized as triple negative breast cancer cells. Since 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.