Combination Chemoprevention of ER-Negative 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。在2003年预计将发生的约40，000例乳腺癌死亡中，12，000 - 15，000例将为ER阴性，在预计的213，000例新的乳腺癌病例中，三分之一将为ER阴性。虽然抗雌激素方法为预防ER表达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药物作为化学预防剂是那些靶向环氧合酶（考克斯）酶和类维生素A受体。特别地，异构体特异性试剂，即选择性考克斯-2抑制剂和类维生素A 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具有降低的毒性。考克斯-2与肿瘤发生密切相关：考克斯-2缺乏可防止实验动物肠道和皮肤肿瘤形成，相反，乳腺靶向考克斯-2过表达可导致小鼠乳腺癌。重要的是，考克斯-2在大约40%的人乳腺癌中表达，特别是在ER阴性的乳腺癌中。考克斯-2阳性也与HER 2/neu过表达相关，其发生在20-30%的人类乳腺癌中。我们已经证明，选择性考克斯-2抑制剂塞来昔布可预防MMTV/neu小鼠实验性ER阴性乳腺癌的形成。RXR选择性类维生素A LGD 1069也延迟了该模型中的肿瘤发作。然而，单独使用这两种药物都不足以完全预防肿瘤形成。该研究的假设是，选择性考克斯-2抑制剂与RXR选择性类维生素A的联合使用比单独使用任何一种药物预防ER阴性乳腺癌更有效。为了检验这一假设，将比较塞来昔布和LGD 1069联合给药的MMTV/neu小鼠、单独接受任一药物的MMTV/neu小鼠和对照动物的肿瘤发生率。此外，将在对照和药物处理动物中比较初始检测后的肿瘤生长速率，以确定药物处理是否降低肿瘤生长。将进行生物学终点试验，以研究观察到的抗癌作用的机制基础，包括增殖、凋亡和血管生成试验。这项研究的结果将为评估这种联合方法在乳腺癌高危女性中的应用提供基础。

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.