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

描述(由申请人提供)：相关性和具体目标 相关性：迫切需要了解乳腺癌的发病机制，特别是在存活率较低的少数民族和服务不足的人群中。这个项目的目的是开发一个全面的乳腺癌研究项目，提供机会来确定用于诊断的新的生物学目标，并跟踪少数族裔和服务不足人群中癌症的进展情况。我们将以以下具体目标完成目标： 具体目标1：乳腺癌组织中CCN蛋白水平及其下游靶点与患者临床参数的关系(第1年)。乳腺癌组织阵列将进行CCN蛋白染色，结果将与种族分组相关，特别是非裔美国人和西班牙裔人口，以及他们的临床信息。这项活动将在CDU进行。此外，我们有乳腺癌细胞株的数据显示，CCN蛋白与整合素结合并激活(3-连环蛋白/TCF和PI3K/AKT/mTOR/4EBP1/SK6通路)。复制的乳腺癌阵列将被染色，以确定这些下游蛋白在患者样本中是否被激活。我们将使用来自国家癌症研究所的大组织阵列；验证将利用来自慈善机构德鲁大学/马丁·路德·金少年-多蒂服务门诊护理中心(前身为金-德鲁医疗中心)的大型且特征良好的乳腺癌石蜡切片。这一目标将证明非裔美国人、拉丁裔和高加索人乳腺癌患者之间是否存在生物学差异。 到目前为止，还没有人发现CCN蛋白的表达水平与乳腺癌的种族或其他临床特征有关。我们之前在RNA水平上的研究引导我们假设，我们将通过免疫组织化学证明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，可以在诊断时对CCN蛋白的表达进行简单的免疫组织化学检测，以提供预后指标，并帮助指导治疗的侵袭性。 特定目的2：研究选择性过表达CCN蛋白在转基因小鼠乳腺组织中的作用(2-3年)。选择性过表达CCN1的转基因小鼠将被创造出来，以研究乳腺癌的体内发展。如果癌症没有发展，这些小鼠将与过度表达ErbB-2(HER-2/neu)的小鼠交配。这些小鼠应该比单独转基因的小鼠更早患上乳腺癌。这些小鼠可用于测试各种化学预防、化疗或其他新的治疗策略。 具体目标3：确定促进乳腺癌细胞转化所必需的CCN1和CCN2结构域(1-2岁)。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靶点。 具体目标4(第2-3年)：探索CCN蛋白在乳腺癌中过度表达的治疗意义。利用在上述特定目的中获得的知识，即CCN蛋白的过表达使乳腺癌细胞对化疗产生耐药，我们将尝试各种治疗措施来阻断CCN刺激通路。 具体目标4A：研究CCN过表达的乳腺癌细胞耐药的范围、程度和原因。特定目的48：抑制表达CCN的乳腺癌中的生长刺激通路。这些方法将包括开发针对CCN蛋白的单抗和/或阻断整合素(CCN蛋白的受体)或阻断CCN蛋白异常刺激的下游通路的显性负性蛋白。 综上所述，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，特别是在我们少数族裔服务的非裔美国人和西班牙裔患者中。这些洞察力将导致临床结果的新的预后指标，以及为这种毁灭性疾病提供新的治疗方法。该项目为CDU的研究人员提供了绝佳的机会，让他们学习基因组学最先进的科学和技术，特别是在创造转基因动物方面。该项目在CDU和Cedars/UCLA同时进行。

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.