Chemoprevention of ER-Negative Breast Cancer

ER 阴性乳腺癌的化学预防

• 批准号: 6908972
• 负责人: Michael B Sporn
• 金额: $ 35.16万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908972
• 关键词: antineoplastics; apoptosis; biomarker; breast neoplasms; cell line; chemoprevention; disease /disorder prevention /control; drug screening /evaluation; epidermal growth factor; epithelium; estrogen receptors; female; gene expression; genetically modified animals; immunocytochemistry; kinase inhibitor; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; tissue /cell culture; western blottings; xenotransplantation

DESCRIPTION (provided by applicant): Our overall goal is to develop new chemopreventive agents and regimens in animal models of estrogen receptor (ER) negative breast cancer, for eventual use to prevent this disease in women at risk. Our specific hypothesis is that the use of combinations of agents will be more practical and efficacious than use of single agents. However, many potentially useful chemopreventive agents have yet to be tested as single drugs for prevention of ER-negative breast cancer, so in a 5 year project, it will be necessary to evaluate these compounds first as single agents, before testing them in combinations. A second major hypothesis is that induction of apoptosis by non-cytotoxic chemopreventive agents in premalignant breast epithelium represents an important mechanism for prevention of ER-negative breast cancer. There are four Specific Aims in the project: Specific Aim 1: to establish a series of chemopreventive agents, to be used either singly or in combinations for prevention of ER-negative breast cancer; it is essential that these agents have known molecular targets. Specific Aim 2: to test the agents in Specific Aim 1 in selected mouse models of ER-negative breast cancer for their chemopreventive activity. Specific Aim 3: to identify useful markers and surrogate end-points, as well as classical histopathologic criteria, for evaluating the activities of agents shown to be useful in Specific Aim 2. Specific Aim 4: to evaluate the ability of the chemopreventive agents discussed in Specific Aim 1 to induce apoptosis in immortalized human breast epithelium, both non-neoplastic and neoplastic. We have assembled a series of preventive agents, including rexinoids, SERMs, vitamin D analogs, PPAR-gamma ligands, chromatin modifiers, and an EGF-receptor kinase inhibitor. These will be tested in several different transgenic and xenograft mouse models. We will establish a histopathologic scoring system for measuring severity of pre-malignant and malignant lesions, and will also use biochemical markers related to cell proliferation, cell differentiation, and invasiveness for evaluating effects of preventive agents. Finally, we will use standard techniques to measure apoptosis in breast epithelial cells in culture as well as in breast lesions in mice. These studies on apoptosis will be supplemented by measuring effects of chemopreventive agents on Myc gene expression.

描述（由申请人提供）： 我们的总体目标是在雌激素受体（ER）阴性乳腺癌动物模型中开发新的化学预防剂和治疗方案，以防止这种疾病的这种疾病。我们的具体假设是，与单一代理的使用相比，使用代理的组合将更实用和有效。但是，许多潜在有用的化学预防剂尚未被作为预防ER阴性乳腺癌的单一药物进行测试，因此在5年的项目中，有必要先将这些化合物作为单个剂进行评估，然后再对其进行组合进行测试。第二个主要假设是，在乳腺癌前上皮中，非毒性化学预防剂诱导凋亡是预防ER阴性乳腺癌的重要机制。该项目中有四个特定的目的：具体目的1：建立一系列化学预防剂，可以单独使用或组合预防ER阴性乳腺癌；这些药物具有已知的分子靶标是至关重要的。特定目的2：在特定目标1中测试特定目标中的药物在某些ER阴性乳腺癌模型中的化学预防活性。特定目的3：确定有用的标记和替代终点以及经典的组织病理学标准，以评估证明在特定目的中有用的试剂的活性2。特定目的4：评估化学预防剂在特定目标1中讨论的特定目标1中的化学反射药物的能力1，以诱导男性乳房乳房的非生产性人乳房上皮和非neoptastic诱导人类乳房乳腺癌。我们组装了一系列预防剂，包括雷克素，Serms，维生素D类似物，PPAR-GAMMA配体，染色质修饰剂和EGF受体激酶激酶抑制剂。这些将在几种不同的转基因和异种移植小鼠模型中进行测试。我们将建立一个组织病理评分系统，用于测量恶性和恶性病变的严重程度，还将使用与细胞增殖，细胞分化和侵入性有关的生化标志物来评估预防剂的作用。最后，我们将使用标准技术来测量培养物以及小鼠乳腺病变中乳腺上皮细胞中的凋亡。这些对凋亡的研究将通过测量化学预防剂对MYC基因表达的影响来补充。