Deguelin in therapy of triple negative breast cancer

描述（由申请人提供）：抗雌激素和芳香化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HER2/neu患者的治疗选择。然而，表达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研究的主要焦点。在我们鉴定天然致癌抑制剂的项目中，我们通过基于机械调节的生物测定的活性引导分馏分离出了deguelin，这是一种存在于非洲植物Mundulea sericea（豆科植物）中的植物化学物质。Deguelin诱导多种癌细胞凋亡，抑制器官培养中乳腺癌前病变的发展，抑制两期皮肤癌中乳头瘤的发展，抑制mnu诱导的乳腺癌中肿瘤的多样性，抑制鸟氨酸脱羧酶的活性。最近，我们观察到它选择性地抑制了四种具有三阴性乳腺癌细胞特征的细胞系的增殖。微阵列分析的初步实验表明，在去胶蛋白处理下，细胞中凋亡和Wnt/ β - catenin信号基因两种独立通路的差异表达。更重要的是，去圭林已被考虑用于肺癌患者的临床试验。本应用中提出的研究将为去圭林在三阴性乳腺癌患者中的转化应用提供一个直接的机会。总体目标是了解去圭林在体外和体内对ER、PR和Her2/neu阴性乳腺癌细胞的作用，并观察去圭林是否可以用作三阴性乳腺癌（TNBC）患者的靶向治疗。具体目标是：1.利用12种市售的乳腺癌细胞系评估去圭林的疗效，这些细胞系代表了乳腺癌的三种主要分类：ER和PR阳性、HER-2扩增和三重（ER、PR、Her2/neu）阴性。目的：探讨小鼠乳腺器官培养（MMOC）中类固醇受体阳性和阴性肿瘤前病变发生过程中去桂林介导的分子事件。2. 采用原位移植模型，观察去圭林对TNBC细胞体内代谢的影响。3. 描述脱胶作用的目标。该结果将为TNBC患者提供一个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. 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.