Aspirin for Breast Cancer Prevention

项目简介：本研究的主要目的是通过小鼠乳腺癌模型，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，我们将确定阿司匹林是否具有与选择性环氧化酶2 （COX-2）抑制剂塞来昔布相当或更高的疗效。我们和其他人之前已经表明，选择性COX-2抑制剂在啮齿动物乳腺癌模型中具有保护作用。这种方法是基于对COX-2在大约40%的人类乳腺癌中过表达的观察，特别是那些er阴性和过表达人表皮生长因子受体2 （HER2/neu）的乳腺癌。然而，最近关于长期使用COX-2抑制剂增加心血管风险的报道削弱了使用这类药物进行癌症化学预防的吸引力。相比之下，COX抑制剂阿司匹林被广泛用于心血管保护，并已被证明对预防结直肠肿瘤有效。我们假设阿司匹林可能对预防乳腺癌同样有效，因此可能提供选择性COX-2抑制剂的替代方案，并且伴随的不良心脏事件风险较小。作为我们假设的第一个测试，我们将使用MMTV/ new小鼠来检测阿司匹林对er阴性乳腺癌的保护能力。肿瘤发生率将在MMTV/新女性给予阿司匹林或塞来昔布与对照组小鼠进行比较。次要终点包括：初始检测后的肿瘤生长速度、肿瘤的多样性和肺转移的频率。将进行生物终点试验，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敲除小鼠的乳腺血管系统明显减少，因此测定药物介导的对乳腺血管生成的影响将是特别有趣的。

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.