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: 6522001
• 负责人: Debra A Tonetti
• 金额: $ 17.5万
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522001
• 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（由申请人提供）：对三苯氧胺（TAM）的耐药性是乳腺癌最常用的内分泌治疗方法，代表了该疾病管理中的一个重要问题。确定TAM耐药分子机制中的关键因素无疑将导致合理的治疗靶点的发展。我们以前曾报道过，蛋白激酶C α（PKC α）稳定转染到T47 D人乳腺癌细胞的结果在一个不依赖于乳腺癌的表型和TAM耐药的肿瘤生长。由这些细胞形成的肿瘤在TAM存在下生长，并在17 β-雌二醇（E2）存在下消退。我们发现纯抗雌激素可以抑制这些TAM耐药肿瘤，这可能对TAM耐药乳腺癌的治疗有重要意义。这些信息现在可以让我们预测内分泌治疗的疗效。例如，如果给予患者TAM治疗，过表达PKCa的肿瘤可能会被刺激生长，因此更合适的治疗可能是雌激素样化合物或纯抗雌激素。然而，我们的T47 D/PKCalpha肿瘤模型不能确定PKCalpha过表达是否发生在TAM暴露之前的患者中，或者是长期TAM治疗的结果。以下特定目的提供了框架，以证实PKCalpha作为TAM治疗失败的预测因子或标志物的作用，并阐明可能参与TAM耐药乳腺癌的下游基因。 1.确定PKCalpha表达是否可预测TAM治疗失败。我们将进行免疫组化分析，以确定PKCalpha表达的石蜡包埋的乳腺癌标本从美国国家癌症研究所的合作乳腺癌组织资源（NCI CBCTR）。 2.确定复发性（TAM耐药）肿瘤相对于原发性肿瘤中PKCa表达是否增加。我们建议研究NMH的林恩塞奇数据库中患者的成对活检，其中原发性和复发性石蜡包埋肿瘤均可通过免疫组织化学确定PKCalpha表达强度和/或频率的变化（如果有）。 3.鉴定在T47 D：A18/PKCalpha细胞和肿瘤中介导非凋亡依赖性表型的PKCa下游差异表达的特异性基因。为了研究PKCa介导的信号通路，我们将利用我们的T47 D：A18/PKCalpha细胞培养物和肿瘤模型来研究通过Atlas基因阵列技术确定的差异基因表达。