Genomic organization of claudin-1 and its assessment in hereditary and sporadic breast cancer

Human claudin-1 is an integral protein component of tight junctions, a stru cture controlling cell-to-cell adhesion and, consequently, regulating parac ellular and transcellular transport of solutes across human epithelia and e ndothelia. 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 ge ne. In order to evaluate the CLDN-1 gene in sporadic and hereditary breast cancer, we have characterized its genomic organization and have screened th e four coding exons for somatic mutations in 96 sporadic breast carcinomas and for germline mutations in 93 breast cancer patients with a strong famil y history of breast cancer. In addition, we have compared the 5'-upstream s equences of the human and murine CLDN1 genes to identify putative promoter sequences and have examined both the promoter and coding regions of the hum an gene in the breast cancer cell lines showing decreased CLDN1 expression. In the sporadic tumors and hereditary breast cancer patients, we have foun d no evidence to support the involvement of aberrant CLDN1 in breast tumori genesis. 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 b e involved in the downregulation of this gene during breast cancer developm ent.