The integrin beta4 subunit has been shown to be involved in various aspects of cancer progression. The aim of the present work was to evaluate the expression of beta4 in primary colon cancers and to investigate the occurrence of a previously identified intestinal nonfunctional variant of beta4 (beta4ctd-) for adhesion to laminin. Immunodetection of beta4 using a panel of antibodies and RT-PCR analyses were performed on series of paired primary colon tumors and corresponding resection margins. The beta4 subunit was found to be significantly overexpressed in cancer specimens at both the protein and transcript levels. Surprisingly, beta4 levels of expression were closely correlated with those of the oncogene c-Myc in individual specimens. In vitro studies of c-Myc overexpression showed an upregulation of beta4 promoter activity. Finally, the beta4ctd- form was identified in the normal proliferative colonic cells but was found to be predominantly absent in colon cancer cells, both in situ and in vitro. We concluded that the beta4ctd- form is lost from colon cancer cells, while the level of the wild-type form of beta4, which is functional for adhesion to laminin, is increased in primary tumors in relation with the expression of c-Myc.