Aspirin for Breast Cancer Prevention

阿司匹林预防乳腺癌

• 批准号: 7038784
• 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: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038784
• 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：这项研究的主要目的是使用小鼠乳腺癌模型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，我们将确定与选择性环氧合酶2（COX-2）抑制剂Celecoxib相比，阿司匹林是否具有可比性或更大的功效。我们和其他人先前已经表明，选择性COX-2抑制剂在啮齿动物乳腺癌模型中具有保护性。这种方法基于大约40％的人乳腺癌（尤其是ER阴性的乳腺癌）以及过表达人表皮生长因子受体2或HER2/NEU的COX-2过表达的观察结果。但是，最近关于长期使用COX-2抑制剂相关的心血管风险增加的报道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，已证明可有效预防结直肠肿瘤。我们假设阿司匹林可能同样有效预防乳腺癌，因此可以为选择性COX-2抑制剂提供替代方案，其不良心脏事件的风险较小。作为我们假设的首次检验，我们将测定使用MMTV/NEU小鼠预防ER阴性乳腺癌的能力。在对照小鼠中给予阿司匹林或塞来氧化的MMTV/NEU雌性中，将比较肿瘤的发病率。次要终点将包括：初始检测后的肿瘤生长速率，肿瘤多重性和肺转移频率。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，包括乳腺前列腺素水平，增殖和凋亡的测定。此外，基于我们最近的数据显示COX-2基因敲除小鼠的乳腺脉管系统大大减少，分析药物介导的对乳腺血管生成的作用的影响尤其令人感兴趣。 相关性：在2005年预计的21万例新乳腺癌病例中，有三分之一将具有ER阴性，预计将导致12-15,000人死亡。抗源性方法为预防ER阳性乳腺癌提供了巨大的希望，但是需要采用新的方法来预防ER阴性癌症。这项研究将检验以下假设：阿司匹林可以使用小鼠乳腺癌模型来减少ER阴性乳腺癌的形成。值得注意的是，在一项前瞻性临床试验中，低剂量阿司匹林已显示可抑制结直肠肿瘤的形成。这尤其重要，因为认为与阿司匹林相关的胃肠道毒性被认为会随着剂量降低而降低。因此，我们拟议的研究的积极结果将奠定对阿司匹林和乳腺癌预防的未来研究的基础，并且由于阿司匹林被广泛用于预防心血管疾病而具有重要的公共卫生影响。