title: Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors).
abstract: Sporadic aggressive fibromatosis (also called desmoid tumor) is a monoclonal proliferation of spindle (fibrocyte-like) cells that is locally invasive but does not metastasize. A similarity to abdominal fibromatoses (desmoids) in familial adenomatous polyposis and a cytogenetic study showing partial deletion of 5q in a subset of aggressive fibromatoses suggests that the adenomatous polyposis coli (APC) gene plays a role in its pathogenesis. APC helps regulate the cellular level of beta-catenin, which is a downstream mediator in Wnt (Wingless) signaling. beta-Catenin has a nuclear function (binds transcription factors) and a cell membrane function (is a component of epithelial cell adherens junctions). Six cases of aggressive fibromatosis of the extremities from patients without familial adenomatous polyposis, or a family history of colon cancer, were studied. Immunohistochemistry, using carboxy and amino terminus antibodies to APC, and DNA sequencing showed that three of the six contained an APC-truncating mutation, whereas normal tissues did not contain a mutation. Western blot and Northern dot blot showed that all six tumors had a higher level of beta-catenin protein than surrounding normal tissues, despite containing similar levels of beta-catenin mRNA. Immunohistochemistry localized beta-catenin throughout the cell in tumor tissues, although it localized more to the periphery in cells from normal tissues. Reverse transcription polymerase chain reaction showed that the tumors expressed N-cadherin but not E-cadherin (a pattern of expression of proteins making up adherens junctions similar to fibrocytes), suggesting that the specific adherens junctions present in epithelial cells are not necessary for beta-catenin function. Increased beta-catenin may cause the growth advantage of cells in this tumor through a nuclear mechanism. The increased protein level, relative to the RNA level, suggests that beta-catenin is degraded at a lower rate compared with normal tissues. In some cases, this is caused by a somatic mutation resulting in a truncated APC protein.
authors.affiliation: Department of Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: B A
authors.initials: BA
authors.lastname: Alman
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: M E
authors.initials: ME
authors.lastname: Pajerski
authors.forename: S
authors.initials: S
authors.lastname: Diaz-Cano
authors.forename: H J
authors.initials: HJ
authors.lastname: Wolfe
mesh_terms: D025601:Adenomatous Polyposis Coli Protein; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005121:Extremities; D018222:Desmoid Tumors / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin