Adenomatous polyposis coli gene mutation alters proliferation through its β-catenin regulatory function in aggressive fibromatosis (desmoid tumor)

Aggressive fibromatosis is a monoclonal proliferation of spindle (fibroblast-like) cells. A subset of lesions contain somatic truncating adenomatous polyposis coil (APC) gene mutations, and all of the lesions contain an elevated beta-catenin protein level, A major function of APC is to regulate beta-catenin protein level, beta-catenin has a dual function in the cell: it is a mem ber of the adherens junction, and it binds transcription factors in the tcf-lef family, transactivating transcription. Cell cultures from aggressive fibromatoses containing an APC mutation were studied, Transient transfection of the full-length APC gene caused decreased proliferation and beta-catenin protein level in these cultures, To determine whether beta-catenin protein level was responsible for the change in proliferation rate, stable transfections of Delta N89 beta-catenin (a stabilized form that is not degraded by APC, but retains all other functions) were achieved in half of the cultures derived from each tumor, whereas the other half were transfected with an empty vector. Transfection of the full-length APC gene in cultures that were stably transfected with Delta N89 beta-catenin did not result in a change in proliferation. The type I promotor of p561ck contains an HMG consensus region, to which members of the tcf-lef family can bind. p561ck was expressed in cultures not transfected with the full-length APC gene and in cultures transfected with the full-length APC gene and Delta N89 beta-catenin, but not In cultures transfected with only the full-length APC gene. These data show that APC truncating mutations give aggressive fibromatosis cells a proliferative advantage through beta-catenin and suggest that beta-catenin acts to transactivate transcription.