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）： 这项研究的主要目标是测试一种预防雌激素受体（ER）阴性乳腺癌的新方法。预计2003年将有约40,000人死于乳腺癌，其中12-15,000人为ER阴性，在预计的213,000个新乳腺癌病例中，三分之一为ER阴性。虽然抗雌激素方法为预防表达 ER 的乳腺癌提供了相当大的希望，但需要新的方法来预防或治疗 ER 阴性乳腺癌。目前正在研究的两类化学预防药物是针对环加氧酶 (COX) 和类视黄醇受体的药物。特别是，异构体特异性药物，即选择性 COX-2 抑制剂和类视黄醇 X 受体 (RXR) 配体，似乎是有效的化学预防剂，相对于非选择性化合物，其毒性较低。 COX-2 与肿瘤发生密切相关：COX-2 缺乏可以防止实验动物肠道和皮肤肿瘤的形成，相反，乳腺靶向 COX-2 过度表达会导致小鼠乳腺癌。重要的是，COX-2 在大约 40% 的人类乳腺癌中表达，特别是在 ER 阴性的乳腺癌中。 COX-2 阳性还与 HER2/neu 过度表达相关，这种情况发生在 20-30% 的人类乳腺癌中。我们已经证明，选择性 COX-2 抑制剂塞来昔布可以防止 MMTV/neu 小鼠实验性 ER 阴性乳腺癌的形成。在此模型中，RXR 选择性视黄醇 LGD1069 也能延迟肿瘤的发生。然而，单独使用这两种药物都不足以完全防止肿瘤形成。这项研究的假设是，选择性 COX-2 抑制剂与 RXR 选择性视黄醇的组合对于预防 ER 阴性乳腺癌比单独使用任一药物更有效。为了检验这一假设，将同时给予塞来昔布和 LGD1069 的 MMTV/neu 小鼠、单独接受任一药物的小鼠以及对照动物的肿瘤发生率进行比较。此外，将在对照动物和药物治疗动物中比较初始检测后的肿瘤生长率，以确定药物治疗是否减少肿瘤生长。将进行生物学终点测定，以研究观察到的抗癌作用的机制基础，包括增殖、细胞凋亡和血管生成的测定。这项研究的结果将为评估这种联合方法对乳腺癌高危女性的疗效提供基础。