Adenomatous Polyposis Coli Gene Mutation Alters Proliferation through its β-Catenin-Regulatory Function in Aggressive Fibromatosis (Desmoid Tumor)

Abstract

Aggressive fibromatosis is a monoclonal proliferation of spindle (fibroblast-like) cells. A subset of lesions contain somatic truncating adenomatous polyposis coli (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 member 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 deltaN89beta-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 deltaN89beta-catenin did not result in a change in proliferation. The type I promotor of p56lck contains an HMG consensus region, to which members of the tcf-lef family can bind. p56lck was expressed in cultures not transfected with the full-length APC gene and in cultures transfected with the full-length APC gene and deltaN89beta-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.

Superficial Fibromatoses are Genetically Distinct from Deep Fibromatoses

“…The ␤-catenin and APC genes are closely interrelated and play a significant role in epithelial neoplasms, best studied in colon cancer (18, 26 -39), but also in deep fibromatoses (19,40) and sarcomas (41). ␤-catenin is an intracellular protein that is regulated by the APC protein.…”

β-Catenin in Soft tissue Sarcomas: Expression is Related to Proliferative Activity in High-Grade Sarcomas

“…The role of ␤-catenin as an oncoprotein has been analyzed so far in a number of epithelial tumors, an increased expression was also shown in aggressive fibromatosis as a representative of mesenchymal tumors (21,22).…”

“…Expression and mutation of ␤-catenin and APC were described in aggressive fibromatosis, a subtype of mesenchymal tumors (21,22). APC mutations in the fibromatoses of FAP syndromes and the loss of chromosome 5q, the chromosomal localization of the APC gene in sporadic desmoid fibromatoses, indicate their relevance for the pathogenesis of fibromatoses as soft tissue tumors (22,23).…”

Invasion and MMP expression profile in desmoid tumours

“…They can occur as sporadic lesions or as part of familial adenomatous polyposis, which is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Sporadic desmoids harbour somatic mutations in either the APC gene or in the b-catenin gene, resulting in b-catenin protein stabilisation (Li et al, 1988;Tejpar et al, 1999). Previously, we demonstrated constitutive TCF activation in primary desmoid cell cultures and showed that b-catenin binds and activates TCF-3 in these tumours (Tejpar et al, 2001).…”