PKC as a Marker in Tamoxifen Resistant Brest Cancer

PKC 作为他莫昔芬耐药性乳腺癌的标志物

• 批准号: 6654404
• 负责人: Debra A Tonetti
• 金额: $ 16.11万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-04 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654404
• 关键词: apoptosis; biological signal transduction; biomarker; breast neoplasms; clinical research; drug resistance; estradiol; gene expression; hormone therapy; human tissue; immunocytochemistry; microarray technology; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; polymerase chain reaction; protein kinase C; tamoxifen; terminal nick end labeling; tissue /cell culture

DESCRIPTION (provided by applicant): Resistance to tamoxifen (TAM), the most often prescribed endocrine treatment for breast cancer, represents a significant problem in the management of the disease. Identification of the key factors involved in the molecular mechanism of TAM resistance will undoubtedly lead to the development of logical therapeutic targets. We have previously reported that stable transfection of protein kinase C alpha (PKCa) into T47D human breast cancer cells results in a hormone-independent phenotype and TAM-resistant tumor growth. Tumors formed from these cells grow in the presence of TAM and regress in the presence of 17Beta-estradiol (E2). Our finding that a pure antiestrogen can inhibit these TAM-resistant tumors may have important implications for the treatment of TAM-resistant breast cancer. This information may now allow us to predict the efficacy of endocrine therapy. For example, tumors overexpressing PKCa may be stimulated to grow if the patient is given TAM therapy, therefore a more appropriate therapy may be an estrogen-like compound or a pure antiestrogen. However our T47D/PKCalpha tumor model cannot determine whether PKCalpha overexpression occurs in patients prior to TAM exposure, or is a result of long-term TAM treatment. The following Specific Aims provide the framework to substantiate the role of PKCalpha as a predictor or as a marker of TAM treatment failure as well as elucidate the downstream genes that may participate in TAM-resistant breast cancer. 1. To determine whether PKCalpha expression is predictive of TAM-treatment failure. We will perform immunohistochemical analysis to determine PKCalpha expression in paraffin-embedded breast cancer specimens obtained from the National Cancer Institute's Cooperative Breast Cancer Tissue Resource (NCI CBCTR). 2. To determine whether PKCa expression increases in recurrent (TAM-resistant) tumors relative to the primary tumor. We propose to study paired biopsies from patients from the Lynn Sage database at NMH where both primary and recurrent paraffin-embedded tumors are available to identify changes, if any, in the intensity and/or frequency of PKCalpha expression by immunohistochemistry. 3. Identify specific genes that are differentially expressed downstream of PKCa that mediate the hormone-independent phenotype in T47D:A18/PKCalpha cells and tumors. To examine the PKCa-mediated signaling pathway we will utilize our T47D:A18/PKCalpha cell culture and tumor model to investigate differential gene expression as determined by Atlas Gene Array technology.

描述(申请人提供)：对他莫昔芬()的耐药性，这是乳腺癌最常开出的内分泌治疗方法，是这种疾病管理中的一个重大问题。明确耐药的分子机制中的关键因素，无疑将有助于制定合理的治疗靶点。我们先前已经报道，稳定地将蛋白激酶Cα(PKCA)导入T47D人乳腺癌细胞会导致激素非依赖的表型和耐药的肿瘤生长。由这些细胞形成的肿瘤在的存在下生长，在17β-雌二醇(E2)的存在下消退。我们发现，单纯的抗雌激素可以抑制这些对耐药的肿瘤，这一发现可能对耐药乳腺癌的治疗具有重要意义。这些信息现在可以让我们预测内分泌治疗的疗效。例如，如果患者接受治疗，过表达PKCA的肿瘤可能会被刺激生长，因此更合适的治疗方法可能是雌激素样化合物或纯抗雌激素。然而，我们的T47D/PKCalpha肿瘤模型无法确定PKCalpha过表达是发生在接触之前的患者中，还是长期治疗的结果。以下特定目的为证实PKCalpha作为治疗失败的预测或标志的作用以及阐明可能参与耐药乳腺癌的下游基因提供了框架。 1.确定PKCalpha的表达是否预示治疗失败。我们将进行免疫组织化学分析，以确定从国家癌症研究所的合作乳腺癌组织资源(NCI CBCTR)获得的石蜡包埋乳腺癌标本中PKCalpha的表达。 2.确定PKCA在复发(耐药)肿瘤中的表达是否高于原发肿瘤。我们建议从NMH的Lynn Sage数据库中研究患者的配对活检组织，其中原发和复发的石蜡包埋肿瘤都可以通过免疫组织化学来识别PKCalpha表达的强度和/或频率的变化。 3.找出在T47D：A18/PKCalpha细胞和肿瘤中介导激素非依赖性表型的PKCA下游差异表达的特定基因。为了研究PKCA介导的信号通路，我们将利用我们的T47D：A18/PKCalpha细胞培养和肿瘤模型来研究Atlas基因阵列技术确定的差异基因表达。