Physical interaction between the lymphoid high mobility group (HMG)‐box architectural transcription factors TCF/LEF and β‐catenin is associated with translocation of the heteromeric complex to the nucleus and regulation of target gene expression. Since formation of molecular complexes among β‐catenin, E‐cadherin, p300^apc and TCF/LEF depends on balanced expression of these constituents, we investigated the biosynthesis of TCF‐1 in colorectal cancer. Here we report detailed analyses of activation and overexpression of lymphoid transcription factor TCF‐1 in human colorectal cancer‐derived cell lines. Northern blot analyses revealed considerable steady‐state expression levels of TCF‐1 mRNA of normal size. Genomic rearrangement of the 5′ flanking region of the TCF‐1 gene was excluded as a cause of ectopic expression. By contrast, CAT‐reporter constructs depending on a 515‐bp T‐cell‐regulated TCF‐1 genomic upstream region were significantly activated in epithelial tumor cells. RT‐PCR analyses revealed a heterogeneic population of mRNA isoforms due to alternative splicing in the TCF‐1 gene. On Western blots of colorectal cancer cells, the TCF‐1‐specific monoclonal antibody 7H3 detected a similar heterogeneous spectrum of TCF‐1 specific polypeptide chains. Interestingly, overexpression of TCF‐1‐specific splice forms correlated with the metastatic behavior of the analyzed cells and with overproduction of lymphoid tyrosine protein kinase p56^lck. We conclude that ectopic expression of the HMG‐box factor TCF‐1 is associated with late events in tumor progression. Int. J. Cancer 72:625–630, 1997. © 1997 Wiley‐Liss, Inc.