Genomic organization of claudin-1 and its assessment in hereditary and sporadic breast cancer
Genomic organization of claudin-1 and its assessment in hereditary and sporadic breast cancer
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DOI：
10.1007/s004390000375
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发表时间：
2000-09-01
期刊：
影响因子：
5.3
通讯作者：
Weber, BHF
中科院分区：
文献类型：
--
作者：
Krämer, F;White, K;Weber, BHF
人claudin-1是紧密连接不可或缺的蛋白质成分，是一种控制细胞间粘附的结构，从而调节溶质在人上皮和内皮细胞间的细胞旁和细胞间运输。最近，从人乳腺上皮细胞（HMECs）中分离到一个CLDN1 cDNA。与在许多乳腺肿瘤和乳腺癌细胞系中低水平或无法检测到的表达相比，HMECs中的CLDN1表达表明CLDN1可能是一种肿瘤抑制基因。为了评估CLDN-1基因在散发性和遗传性乳腺癌中的作用，我们对其基因组组织进行了表征，并筛选了96例散发性乳腺癌中体细胞突变的4个编码外显子和93例有强烈乳腺癌家族史的乳腺癌患者的种系突变。此外，我们比较了人类和小鼠CLDN1基因的5'上游序列，以确定可能的启动子序列，并在显示CLDN1表达减少的乳腺癌细胞系中检测了人类基因的启动子和编码区。在散发性肿瘤和遗传性乳腺癌患者中，我们没有发现证据支持异常CLDN1参与乳腺肿瘤的发生。同样，在乳腺癌细胞系中，没有发现启动子或编码序列的遗传改变，这可以解释CLDN1表达的丧失。在乳腺癌的发展过程中，其他调控或表观遗传因素可能参与了该基因的下调。
Human claudin-1 is an integral protein component of tight junctions, a structure controlling cell-to-cell adhesion and, consequently, regulating paracellular and transcellular transport of solutes across human epithelia and endothelia. Recently, a claudin-1 (CLDN1) cDNA has been isolated from human mammary epithelial cells (HMECs). CLDN1 expression in HMECs, in contrast to low or undetectable levels of expression in a number of breast tumors and breast cancer cell lines, points to CLDN1 as a possible tumor-suppressor gene. In order to evaluate the CLDN-1 gene in sporadic and hereditary breast cancer, we have characterized its genomic organization and have screened the four coding exons for somatic mutations in 96 sporadic breast carcinomas and for germline mutations in 93 breast cancer patients with a strong family history of breast cancer. In addition, we have compared the 5'-upstream sequences of the human and murine CLDN1 genes to identify putative promoter sequences and have examined both the promoter and coding regions of the human gene in the breast cancer cell lines showing decreased CLDN1 expression. In the sporadic tumors and hereditary breast cancer patients, we have found no evidence to support the involvement of aberrant CLDN1 in breast tumorigenesis. Likewise, in the breast cancer cell lines, no genetic alterations in the promoter or coding sequences have been identified that would explain the loss of CLDN1 expression. Other regulatory or epigenetic factors may be involved in the downregulation of this gene during breast cancer development.