Aspirin for Breast Cancer Prevention

阿司匹林预防乳腺癌

• 批准号: 7126753
• 负责人: LOUISE R HOWE
• 金额: $ 8.2万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126753
• 关键词: angiogenesis; antineoplastics; apoptosis; aspirin; breast neoplasms; cancer prevention; cardiovascular pharmacology; cell proliferation; chemoprevention; cyclooxygenase inhibitors; disease /disorder model; estrogen receptors; genetically modified animals; immunocytochemistry; laboratory mouse; metastasis; mouse mammary tumor virus; neoplasm /cancer chemotherapy; neoplastic growth; nonhuman therapy evaluation; nonsteroidal antiinflammatory agent; polymerase chain reaction

DESCRIPTION (provided by applicant): Project Summary: The main goal of this research is to test the ability of aspirin to prevent estrogen receptor (ER)-negative breast cancer, using a mouse breast cancer model. In particular, we will establish whether aspirin has comparable or greater efficacy than the selective cyclooxygenase 2 (COX-2) inhibitor celecoxib. We and others have previously shown that selective COX-2 inhibitors are protective in rodent breast cancer models. This approach was based on observations of COX-2 overexpression in approximately 40% of human breast cancers, particularly those that are ER-negative and those that overexpress human epidermal growth factor receptor 2, or HER2/neu. However, recent reports of increased cardiovascular risk associated with prolonged use of COX-2 inhibitors diminish the attractiveness of using this class of drugs for cancer chemoprevention. In contrast, the COX inhibitor aspirin is widely used for cardiovascular protection, and has proven effective for preventing colorectal neoplasia. We hypothesize that aspirin may be similarly effective for preventing breast cancer, and may thus provide an alternative to selective COX-2 inhibitors with less attendant risk of adverse cardiac events. As a first test of our hypothesis, we will assay the ability of aspirin to protect against ER-negative breast cancer using MMTV/neu mice. Tumor incidence will be compared in MMTV/neu females administered either aspirin or celecoxib with that in control mice. Secondary endpoints will include: tumor growth rate after initial detection, tumor multiplicity, and frequency of lung metastases. Biological endpoint assays will be performed to investigate the mechanistic basis of observed anti-cancer effects, including assays of mammary prostaglandin levels, proliferation, and apoptosis. Additionally, based on our recent data showing profoundly reduced mammary vasculature in Cox-2 knockout mice, it will be of particular interest to assay drug-mediated effects on mammary angiogenesis. Relevance: Of the 210,000 new breast cancer cases predicted for 2005, one-third will be ER-negative, resulting in an anticipated 12-15,000 deaths. Antiestrogenic approaches offer considerable promise for preventing ER-positive breast cancers, but new approaches are required to prevent ER-negative cancers. This research will test the hypothesis that aspirin can reduce formation of ER-negative breast cancers, using a mouse breast cancer model. Notably, low-dose aspirin has been shown to suppress colorectal tumor formation in a prospective clinical trial. This is particularly important because aspirin-associated gastrointestinal toxicity is thought to diminish with decreasing dose. Thus, a positive result in our proposed study would lay the foundation for future studies of aspirin and breast cancer prevention, and would have important public health implications since aspirin is widely used to protect against cardiovascular disease.

描述（由申请人提供）： 项目摘要：本研究的主要目标是使用小鼠乳腺癌模型来测试阿司匹林预防雌激素受体（ER）阴性乳腺癌的能力。特别是，我们将确定阿司匹林是否具有与选择性环氧合酶 2 (COX-2) 抑制剂塞来昔布相当或更强的功效。我们和其他人之前已经证明，选择性 COX-2 抑制剂对啮齿动物乳腺癌模型具有保护作用。该方法基于对大约 40% 人类乳腺癌中 COX-2 过度表达的观察，特别是 ER 阴性乳腺癌和过度表达人类表皮生长因子受体 2（或 HER2/neu）的乳腺癌。然而，最近有报道称，长期使用 COX-2 抑制剂会增加心血管风险，这降低了使用此类药物进行癌症化学预防的吸引力。相比之下，COX抑制剂阿司匹林广泛用于心血管保护，并已被证明可有效预防结直肠肿瘤。我们假设阿司匹林对于预防乳腺癌可能同样有效，因此可能提供选择性 COX-2 抑制剂的替代品，且不良心脏事件的风险较小。作为对我们假设的第一次检验，我们将使用 MMTV/neu 小鼠测定阿司匹林预防 ER 阴性乳腺癌的能力。将施用阿司匹林或塞来考昔的 MMTV/neu 雌性小鼠与对照小鼠的肿瘤发生率进行比较。次要终点包括：初次检测后的肿瘤生长率、肿瘤多重性和肺转移频率。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，包括乳腺前列腺素水平、增殖和细胞凋亡的测定。此外，根据我们最近的数据显示 Cox-2 敲除小鼠的乳腺脉管系统显着减少，因此检测药物介导的乳腺血管生成作用将特别令人感兴趣。 相关性：预计 2005 年将有 210,000 例新乳腺癌病例，其中三分之一为 ER 阴性，预计将导致 12-15,000 例死亡。抗雌激素方法为预防 ER 阳性乳腺癌提供了广阔的前景，但需要新的方法来预防 ER 阴性癌症。这项研究将使用小鼠乳腺癌模型来检验阿司匹林可以减少 ER 阴性乳腺癌形成的假设。值得注意的是，一项前瞻性临床试验已证明低剂量阿司匹林可以抑制结直肠肿瘤的形成。这一点尤其重要，因为阿司匹林相关的胃肠道毒性被认为会随着剂量的减少而减弱。因此，我们提出的研究中的积极结果将为阿司匹林和乳腺癌预防的未来研究奠定基础，并且由于阿司匹林广泛用于预防心血管疾病，因此将具有重要的公共健康意义。