CSVTCG-SPECIFIC THROMBOSPONDIN RECEPTOR IN BREAST CANCER

乳腺癌中的 CSVTCG 特异性血小板反应蛋白受体

• 批准号: 6032856
• 负责人: GEORGE Paul TUSZYNSKI
• 金额: $ 1.86万
• 依托单位: MCP HAHNEMANN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-27 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6032856
• 关键词: antireceptor antibody; antisense nucleic acid; athymic mouse; breast neoplasms; cell adhesion; cell growth regulation; circulating neoplastic cell; human subject; mammary epithelium; monoclonal antibody; neoplasm /cancer invasiveness; protein sequence; protein structure function; receptor expression; recombinant proteins; thrombospondins; transfection

We have recently shown that the CSVTCG (cysteine, serine, valine, threonine, cysteine, glycine) sequence of TSP, a natrix protein that has been implicated in mechanisms of malignancy, functions as a tumor cell adhesion domain and CSVTCG peptides as well as anti-CSVTCG antibodies have anti-metastatic activity in a murine model of lung metastasis. We have also isolated a novel CSVTCG-specific tumor cell adhesion receptor and shown by immunohistochemical staining of human breast tumors that the receptor localizes to malignant ductal epithelium while no staining of epithelium in normal and benign tissues was observed. These studies suggest that the CSVTCG-specific receptor may function to promote the invasive behavior of breast epithelium and contribute to the development of malignancy. To test this hypothesis, we propose to retrospectively correlate the expression of the CSVTCG-specific receptor in human breast tumor samples stored in the MCP tumor bank with patient survival and the presence of metastases in patients at time of diagnosis. In addition, we will determine if patients with borderline cancers such as in situ carcinoma and benign tumors with hyperplasia (which expressed receptor) went on to develop malignant disease. Monoclonal antibodies against the CSVTCG-specific receptor will be prepared in order to further characterize the function and structure of the receptor in tumor cell invasion. The primary structure of human and mouse CSVTCG-receptor will be obtained by cloning their cDNA. The receptor structures as they relate to functions will be determined by a) expression of the receptor, b) construction of chimeric and mutated molecules c) and fragmentation of the receptor. The in vitro and in vivo role of the receptor in breast tumor progression will be assessed by studying the characteristics of receptOr (sense and antisense) in transfected normal and neoplastic breast epithelial cells in tissue culture and in athymic mice. These studies should provide information on the role of the CSVTCG-specific thrombospondin receptor in breast cancer tumor progression and whether the expression of the receptor in breast epithelium can be used diagnostically to predict the invasive phenotype.

我们最近已经表明，CSVTCG（半胱氨酸，丝氨酸，缬氨酸， 苏氨酸、半胱氨酸、甘氨酸）序列，TSP是一种游游蛋白， 与恶性肿瘤的机制有关， 粘附结构域和CSVTCG肽以及抗CSVTCG抗体具有 在肺转移的鼠模型中的抗转移活性。 我们有 还分离了一种新的CSVTCG特异性肿瘤细胞粘附受体， 人类乳腺肿瘤的免疫组织化学染色显示， 受体定位于恶性导管上皮细胞， 观察正常和良性组织中的上皮。这些研究 提示CSVTCG特异性受体可能具有促进 乳腺上皮的侵袭行为，并有助于发展 恶性肿瘤为了验证这一假设，我们建议回顾性地 与人乳腺中CSVTCG特异性受体的表达相关 储存在MCP肿瘤库中的肿瘤样品与患者存活率和 诊断时患者存在转移。另外我们 将确定是否有边缘性癌症患者，如原位癌， 癌和良性肿瘤伴增生（表达受体） 发展成恶性疾病单克隆抗体 将制备CSVTCG特异性受体，以进一步表征 受体在肿瘤细胞侵袭中的功能和结构。的 人和小鼠CSVTCG受体的一级结构将通过以下方法获得： 克隆它们的cDNA。与功能相关的受体结构 将由a）受体的表达，B） 嵌合和突变分子c）和受体的片段化。的 受体在乳腺肿瘤进展中的体外和体内作用将 通过研究接受者的特征（感觉和 反义）在转染的正常和肿瘤性乳腺上皮细胞中的表达， 组织培养和在无胸腺小鼠中。这些研究将提供 关于CSVTCG特异性血小板反应蛋白受体在 乳腺癌的肿瘤进展和是否表达受体 乳腺上皮细胞中的表达可用于诊断， 表型