Chemoprevention of ER-Negative Breast Cancer

描述(由申请人提供)： 我们的总体目标是在雌激素受体(ER)阴性乳腺癌的动物模型中开发新的化学预防药物和方案，最终用于预防高危女性的这种疾病。我们的具体假设是，联合使用药物将比使用单一药物更实用和有效。然而，许多潜在有用的化学预防药物尚未作为预防ER阴性乳腺癌的单一药物进行测试，因此在一个5年的项目中，有必要首先评估这些化合物作为单一药物，然后再联合测试它们。第二个主要假设是，非细胞毒性化学预防药物诱导癌前乳腺上皮细胞凋亡是预防ER阴性乳腺癌的重要机制。该项目有四个具体目标：具体目标1：建立一系列单独或联合使用的化学预防药物，用于预防ER阴性的乳腺癌；这些药物必须具有已知的分子靶点。特定目标2：在选定的ER阴性乳腺癌小鼠模型中测试特定目标1中的药物的化学预防活性。具体目标3：确定有用的标记物和替代终点，以及经典的组织病理学标准，以评估在特定目标2中被证明有用的药物的活性。具体目标4：评估在特定目标1中讨论的化学预防药物诱导永生化的人乳腺上皮细胞凋亡的能力，包括非肿瘤和肿瘤。我们已经组装了一系列的预防药物，包括Rexinoid、SERM、维生素D类似物、PPAR-Gamma配体、染色质修饰剂和EGF受体激酶抑制剂。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。我们将建立衡量癌前病变和癌前病变严重程度的组织病理学评分系统，并将使用与细胞增殖、细胞分化和侵袭性相关的生化指标来评估预防性药物的效果。最后，我们将使用标准技术来测量培养中的乳腺上皮细胞以及小鼠乳腺病变中的细胞凋亡。这些关于细胞凋亡的研究将通过测量化学预防药物对Myc基因表达的影响来补充。

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.