4.1N基因在乳腺癌转移中的生物学作用和分子机制研究

Breast cancer is the most common form of cancer among women. Since the breast cancer-related death is mainly due to its metastasis, it is very important to understand the molecular mechanisms for breast cancer metastasis. Members of protein 4.1 family (4.1R, 4.1B, 4.1G and 4.1N) that link transmembrane proteins to the actin cytoskeleton, have recently emerged as tumor associated genes. Our preliminary data demonstrated that expression of 4.1N was lost in the poorly differentiated breast cancer tissues. Consistent with clinical data, while 4.1N is expressed and co-localized with E-cadherin and beta-catenin in non-metastatic breast cancer cell lines such as MCF-7 and T-47D, its expression is lost in the metastatic breast cancer cell lines such as MDA-MB-231 and MDA-MD-453. These findings together suggest that loss of 4.1N expression may be associated with breast cancer metastasis. In this application, we will examine the effect of 4.1N on cell adhesion and invasion by either overexpressing 4.1N in MDA-MB-231 and MDA-MD-453 cells or knocking down 4.1N in MCF-7 and T-47D cells. We will examine whether there is mutation, promoter hyper-methylation or loss of heterozygosity in 4.1N gene to understand the genetic mechanisms leading to the loss of 4.1N expression. We will also explore the molecular mechanisms by which 4.1N modulates cell-cell adhesion. Finally, we will examine the expression of 4.1N in a large cohort of human breast cancer samples to establish to correlation between loss of 4.1N expression and breast cancer metastasis. Establishment of 4.1N as a breast cancer metastasis-associated gene and understanding of its molecular mechanism may have applications for the diagnosis, prognosis and treatment of breast cancer.

乳腺癌是世界上最严重危害女性健康的恶性肿瘤。乳腺癌的转移严重患者生命。阐明乳腺癌转移的分子机制极其重要。近年研究发现4.1N是一个新的肿瘤相关基因。本课题组发现4.1N在低分化有转移潜能的乳腺癌组织中表达下调或缺失。还发现4.1N在非转移性的乳腺癌细胞株中有表达，并与E-cadherin和catenin共定位，但是在有转移性的乳腺癌细胞株中4.1N表达缺失，这些结果高度提示4.1N缺失可能与乳腺癌转移存在密切相联。.本课题拟在不同乳腺癌细胞中导入或敲除4.1N，从功能上正反两方面检测4.1N对乳腺癌细胞黏附和迁移的影响。从遗传学上探讨4.1N在乳腺癌中的失活机制，弄清其是否存在突变、杂合缺失及起动子甲基化；在分子水平上探讨4.1N与黏附连接分子E-cadherin和catenins的相互作用; 从临床上探讨4.1N表达与乳腺癌转移的相关性。本研究将阐明4.1N在乳腺癌转移中的作用及机制

乳腺癌是世界上最严重危害女性健康的恶性肿瘤。乳腺癌的转移严重患者生命。阐明乳腺癌转移的分子机制极其重要。近年研究发现4.1N 是一个新的肿瘤相关基因。本课题组发现4.1N 在低分化有转移潜能的乳腺癌组织中表达下调或缺失。还发现4.1N 在非转移性的乳腺癌细胞株中有表达，并与E-cadherin 和catenin 共定位，但是在有转移性的乳腺癌细胞株中4.1N 表达缺失，这些结果表明4.1N 缺失可能与乳腺癌转移存在密切相联。课题组通过在不同乳腺癌细胞中导入或敲除4.1N，从功能上正反两方面检测4.1N 对乳腺癌细胞黏附和迁移的影响，探讨4.1N 在乳腺癌中的失活分子机制，发现1/3肿瘤转移后病人的4.1N存在缺失现象。在分子水平上探讨4.1N 与迁移相关信号分子见的调控关系。