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From the Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany
Most colorectal cancers have loss-of-function mutations in the adenomatosis polyposis coli (APC) tumor suppressor gene. This leads to the accumulation of nuclear ß-catenin, which, together with the DNA-binding protein TCF-4, functions as a transcriptional activator. The recently defined target genes c-myc, cyclin D1, and matrilysin are responsible for tumor proliferation or malignant progression and explain the oncogenic potential of nuclear ß-catenin. To investigate its role in early colon carcinogenesis, we analyzed the expression of ß-catenin, its target gene c-myc, and the proliferative activity in 88 colorectal adenomas of varying size and grade of dysplasia. The results revealed i) the most significant correlation of nuclear ß-catenin and c-myc expression was not with the grade of dysplasia but with the size of the colon adenoma; ii) perfect correlation of nuclear ß-catenin and c-myc expression; iii) no significant correlation of adenoma size with the proliferative activity; and iv) no significant correlation of proliferative activity and the nuclear expression of ß-catenin and c-myc. These results imply that APC mutations have additional ß-catenin-independent functions; APC mutations alone are not sufficient for nuclear overexpression of ß-catenin; and nuclear ß-catenin has additional important functions for exceeding a threshold tumor size.
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