DYSREGULATION OF THE E-CADHERIN CATENIN COMPLEX BY IRREVERSIBLE MUTATIONS IN HUMAN CARCINOMAS/

The different proteins of the E-cadherin/catenin cell-cell adhesion co mplex are believed to play a predominant role in carcinogenesis. Aberr ant expression of these proteins has been found in many different huma n carcinomas, indicating abnormal regulation. In general, inactivating mutations of the human E-cadherin gene are rare; they are, however, h ighly frequent in infiltrating lobular breast carcinomas and in diffus e gastric carcinomas. These mutations mostly occur in combination with loss of heterozygosity (LOH) of the wild-type allele. Mutations were found at very early non-invasive stages, thus associating E-cadherin m utations with loss of growth control and defining E-cadherin as a real tumour suppressor for these particular tumour types. Defects affectin g both alleles of the alpha E-catenin gene have been found in differen t human carcinoma cell lines, resulting in the loss of E-cadherin-medi ated cell-cell adhesion. Mutations of the beta-catenin gene in colon t umours and melanomas were found to result in an accumulation of the pr otein in the cytosol. Upon translocation to the nucleus, this beta-cat enin enhances TCF/LEF-dependent transcriptional activity. This suggest s that mutated beta-catenin can act as an oncogene in these particular tumour types. The multiple interaction partners of beta-catenin are k nown to be involved in signal transduction, actin organization, protei n phosphorylation or transcriptional regulation. This makes this prote in an intriguing alternative target for either activation or inactivat ion in human cancer types characterized by frequent E-cadherin or APC deficiencies.