Combination Chemoprevention of ER-Negative Breast Cancer

ER 阴性乳腺癌的联合化学预防

• 批准号: 6804024
• 负责人: LOUISE R HOWE
• 金额: $ 8.4万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804024
• 关键词: angiogenesis; apoptosis; breast neoplasms; cancer prevention; cancer risk; chemoprevention; combination chemotherapy; drug interactions; drug screening /evaluation; enzyme inhibitors; enzyme linked immunosorbent assay; female; high performance liquid chromatography; laboratory mouse; liquid chromatography mass spectrometry; neoplastic growth; nonhuman therapy evaluation; prostaglandin endoperoxide synthase; receptor expression; retinoids; vitamin receptor; vitamin therapy; western blottings

DESCRIPTION (provided by applicant): The main goal of this research is to test a novel approach for preventing estrogen receptor (ER) -negative breast cancer. Of the approximately 40,000 deaths predicted to occur in 2003 due to breast cancer, 12-15,000 will be ER-negative, and of the anticipated 213,000 new breast cancer cases, one third will be ER-negative. While antiestrogenic approaches offer considerable promise for preventing ER-expressing breast cancers, new approaches are required to prevent or treat ER-negative breast cancers. Two drug classes currently under investigation as chemopreventive agents are those targeting cyclooxygenase (COX) enzymes and retinoid receptors. In particular, isoform-specific agents, namely selective COX-2 inhibitors and retinoid X receptor (RXR) ligands, appear to be effective chemopreventives with reduced toxicity relative to non-selective compounds. COX-2 is strongly implicated in tumorigenesis: COX-2 deficiency protects against intestinal and skin tumor formation in experimental animals, and, conversely, mammary-targeted COX-2 overexpression causes breast cancer in mice. Importantly, COX-2 is expressed in approximately 40% of human breast cancers, particularly in those which are ER-negative. COX-2 positivity also correlates with HER2/neu overexpression, which occurs in 20-30% of human breast cancers. We have shown that the selective COX-2 inhibitor celecoxib protects against the formation of experimental ER-negative breast cancer in MMTV/neu mice. The RXR-selective retinoid LGD1069 also delays tumor onset in this model. However, neither agent alone is sufficient to totally prevent tumor formation. The hypothesis underlying the proposed study is that the combination of a selective COX-2 inhibitor with an RXR-selective retinoid will be more effective than either agent alone for preventing ER-negative breast cancer. To test this hypothesis, tumor incidence will be compared in MMTV/neu mice administered both celecoxib and LGD1069, with those receiving either agent alone, and with control animals. Additionally, tumor growth rates following initial detection will be compared in control and drug-treated animals to determine if tumor growth is decreased by drug treatment. Biological endpoint assays will be performed to investigate the mechanistic basis of observed anticancer effects, including assays of proliferation, apoptosis, and angiogenesis. The results of this study will provide the basis for evaluating this combination approach in women at high risk for breast cancer.

描述（由申请人提供）： 这项研究的主要目的是测试一种预防雌激素受体（ER）阴性乳腺癌的新方法。在2003年由于乳腺癌而预计将发生的大约40,000例死亡中，有12-15,000人将具有ER阴性，并且预期的213,000例新的乳腺癌病例将是ER-SINGATED。虽然抗源性方法为防止表达ER的乳腺癌提供了巨大的希望，但需要新的方法来预防或治疗ER阴性乳腺癌。目前正在研究的两种药物类别是化学预防剂是靶向环氧酶（COX）酶和类维生素类动物受体的药物。尤其是，同工型特异性药物，即选择性COX-2抑制剂和类维生素X受体（RXR）配体，似乎是有效的化学预兆，相对于非选择性化合物，毒性降低。 COX-2与肿瘤发生密切相关：COX-2缺乏症可以预防实验动物中的肠道和皮肤肿瘤形成，相反，乳腺靶向的COX-COX COX-COX-COX-COX-COX-COX-COX-COX-COX-COX-COX-COX-COX-COX-2导致小鼠的乳腺癌。重要的是，大约40％的人类乳腺癌表达了COX-2，特别是在ER阴性的乳腺癌中。 COX-2阳性还与HER2/NEU过表达相关，这发生在20-30％的人乳腺癌中。我们已经表明，选择性COX-2抑制剂Celecoxib可以保护MMTV/NEU小鼠中实验性ER阴性乳腺癌的形成。 RXR选择性类维生素LGD1069也延迟了该模型中的肿瘤发作。但是，单独的药物都足以完全防止肿瘤形成。拟议的研究的基本假设是，选择性COX-2抑制剂与RXR选择性类维生素类动物的组合将比单独使用任何一种药物更有效，以防止ER阴性乳腺癌。为了检验该假设，将在塞来氧化和LGD1069施用的MMTV/NEU小鼠中比较肿瘤的发病率，单独接受任何药物和对照动物。此外，将在对照和药物处理的动物中比较初始检测后的肿瘤生长速率，以确定药物治疗是否降低肿瘤的生长。将进行生物终点测定，以研究观察到的抗癌作用的机械基础，包括增生，凋亡和血管生成的测定。这项研究的结果将为评估这种乳腺癌高风险女性的这种组合方法提供基础。