Transactivation of the Multidrug Resistance 1 Gene by T-Cell Factor 4/β-Catenin Complex in Early Colorectal Carcinogenesis

The mutational inactivation of a tumor suppressor gene, adenomatous polyposis coli ( APC ), results in the accumulation of cytoplasmic β-catenin protein and the activation of T-cell factor (TCF)/lymphoid enhancer factor transcriptional factors. A colorectal carcinoma cell line, DLD-1, was engineered to suppress transactivation by the TCF4/β-catenin complex in a dominant-negative manner under the strict control of the tetracycline regulatory system. A large-scale comparison of the expression profiles, using two-color fluorescence hybridization of cDNA microarray, led to the identification of MDR1 as a target gene of the TCF4/β-catenin complex. Luciferase reporter and gel retardation assays revealed the TCF4/β-catenin responsive elements in the promoter of the human MDR1 gene. Corresponding to the accumulation of β-catenin, expression of the MDR1 gene product was steadily up-regulated in adenomas and adenocarcinomas of 10 patients with familial adenomatous polyposis. In combination with cell proliferative activities of c-myc and cyclin D1, MDR1 may initiate colorectal tumorigenesis by suppressing cell death pathways programmed in intestinal epithelial cells.