Charles Drew University/UCLA Cancer Center Partnership to Eliminate Cancer Health

描述（由申请人提供）：相关性和具体目的 相关性：迫切需要了解乳腺癌的发病机制，特别是在少数民族和服务不足的人群中，他们的生存率很低。该项目的目的是开发一个全面的乳腺癌研究项目，提供机会，以确定新的诊断生物靶点，并遵循癌症的进展，以应对少数民族和服务不足的人群的治疗。我们将通过以下具体目标实现我们的目标： 具体目标1：将乳腺癌中CCN蛋白和下游靶标的水平与患者的临床参数相关联（第1年）。将对乳腺癌组织阵列进行CCN蛋白染色，并将结果与种族分组（特别是非洲裔美国人和西班牙裔人群）及其临床信息相关联。该活动将在CDU进行。此外，我们有乳腺癌细胞系数据显示，CCN蛋白结合整合素并激活β-连环蛋白/TCF和PI 3 K/AKT/mTOR/4 EBP 1/SK 6通路。将对复制的乳腺癌阵列进行染色，以确定这些下游蛋白质是否在患者样本中被激活。我们将使用来自国家癌症研究所的大型组织阵列;验证将利用来自德鲁大学慈善机构/马丁·路德·金青年多服务门诊护理中心（以前称为金德鲁医学中心）的大型和特征良好的乳腺癌石蜡块。这一目标将证明非洲裔美国人、拉丁裔和白人乳腺癌患者之间是否存在生物学差异。 到目前为止，还没有人将CCN蛋白的表达水平与乳腺癌的种族或其他临床特征相关联。我们先前在RNA水平的研究使我们假设，我们将通过免疫组织化学显示CCN蛋白水平将是预示疾病侵袭性的独立预后标志物。如果我们是正确的，一个简单的免疫组化检测CCN蛋白的表达可以在诊断时进行，以提供预后指标，并帮助指导治疗的积极性。 具体目标2：研究CCN蛋白在转基因小鼠乳腺组织中选择性过表达的影响（2-3年）。将建立选择性过表达CCN 1的转基因小鼠来研究乳腺癌的体内发展。如果癌症没有发展，这些小鼠将与过表达ErbB-2（Her-2/neu）的小鼠交配。这些小鼠应该比单独的转基因小鼠更早患乳腺癌。这些小鼠可用于测试各种化学预防、化学治疗或其他新的治疗策略。 具体目标3：确定增强乳腺癌细胞转化所必需的CCN 1和CCN 2结构域（第1-2年）。了解促进乳腺癌生长的关键CCN基序将为抑制乳腺癌生长提供未来的目标。 具体目标4（2-3年）：探索乳腺癌中CCN蛋白过表达的治疗意义。利用在前面的特定目标中获得的知识，知道CCN蛋白的过表达使乳腺癌细胞对化疗具有抗性，我们将尝试各种治疗措施来阻断CCN刺激途径。 具体目标4A：研究CCN过表达乳腺癌细胞中化疗耐药的范围、程度和原因。具体目标48：抑制CCN表达乳腺癌中的生长刺激途径。这些方法将包括开发靶向CCN蛋白和/或显性阴性蛋白的单克隆抗体，所述显性阴性蛋白阻断整联蛋白（CCN蛋白的受体）或阻断由CCN蛋白异常刺激的下游途径。 总之，拟议的研究将为CCN蛋白在乳腺癌中发挥的关键作用提供独特的见解，特别是在我们少数服务的非洲裔美国人和西班牙裔患者中。这些见解应该导致新的临床预后指标，以及提供新的治疗方法，这种毁灭性的疾病。该项目为CDU的研究人员提供了极好的机会，学习基因组学的最先进的科学和技术，特别是在创造转基因动物方面。该项目同时在CDU和Cedars/UCLA运行。

DESCRIPTION (provided by applicant): Relevance and Specific Aims Relevance: There is a critical need to understand the pathogenesis of breast cancer, in particular in minority and underserved populations who have poor survival. The purpose of this project is to develop a comprehensive breast cancer research project that provides the opportunity to identify novel biological targets for diagnosis and to follow progression of cancer in response to therapy in Minority and Underserved populations. We will accomplish our goal with the following specific aims: Specific Aim 1: Associate levels of CCN proteins and downstream targets in breast cancers with clinical parameters of the patients (Year 1). Breast cancer tissue arrays will be stained for CCN proteins and results will be correlated with ethnic grouping, especially African American and Hispanic populations, as well as their clinical information. This activity will be performed at CDU. Also, we have breast cancer cell line data that shows that CCN proteins bind to integrins and activate the (3-catenin/TCF and PI3K/AKT/mTOR/4EBP1/ SK6 pathways. Replicate breast cancer arrays will be stained to determine if these downstream proteins are activated in patient samples. We will use large tissue arrays from National Cancer Institute; validation will take advantage of large and well-characterized breast cancer paraffin blocks from Charities Drew University/ Martin Luther King Junior-MuIti Service Ambulatory Care Center (formerly known as the King-Drew Medical Center). This aim will demonstrate if there are biological differences between African American, Latina, and Caucasian breast cancer patients. To date, no one has associated level of expression of CCN proteins and ethnic group or other clinical characteristics of breast cancer. Our prior studies at the RNA level lead us to hypothesize that we will show by immunohistochemistry that levels of CCN proteins will be independent prognostic markers that foreshadow the aggressiveness of the disease. If we are correct, a simple immunohistochemical test for expression of CCN proteins can be performed at diagnosis to provide an indicator of prognosis and help direct the aggressiveness of therapy. Specific Aim 2: Study the effects of selective overexpression of CCN proteins in breast tissue of transgenic mice (Years 2-3). Transgenic mice that selectively overexpress CCN1 will be created to study the in vivo development of breast cancer. If cancers do not develop, these mice will be mated with mice that overexpress ErbB-2 (Her-2/neu). These mice should develop breast cancer at an earlier age than either transgenic alone. These mice can be used to test various chemopreventive, chemotherapeutic or other novel therapeutic strategies. Specific Aim 3: Identify domains of CCN1 and CCN2 necessary to enhance transformation of breast cancer cells (Years 1-2). Understanding the critical CCN motifs that enhance breast cancer growth will provide future targets for inhibiting breast cancer growth. Specific Aim 4 (Year 2-3): Explore the therapeutic implications of overexpression of CCN proteins in breast cancer. Taking advantage of the knowledge garnered in the preceding Specific Aims knowing that overexpression of CCN proteins make the breast cancer cells resistant to chemotherapy, we will try various therapeutic measures to block the CCN stimulatory pathways. Specific Aim 4A: Investigate the range, magnitude, and cause of chemo-resistance in CCN overexpressing breast cancer cells. Specific Aim 48: Inhibit the growth stimulating pathways in CCN expressing breast cancers. These approaches will include developing monoclonal antibodies that target CCN proteins and/or dominant negative proteins that block integrins (receptors of CCN proteins) or block the downstream pathways that are aberrantly stimulated by the CCN proteins. Taken together, the proposed studies will provide unique insights into the pivotal role that CCN proteins play in breast cancer especially in our minority served African American and Hispanic patients. These insights should lead to novel prognostic indicators of clinical outcome, as well as provide new therapeutic approaches to this devastating disease. The project offers outstanding opportunities for the CDU researchers to learn state of the art science and techniques in genomics in general, and specifically in the creation of transgenic animals. This project is run concurrently at CDU and Cedars/UCLA.