title: A common human skin tumour is caused by activating mutations in beta-catenin.
abstract: WNT signalling orchestrates a number of developmental programs. In response to this stimulus, cytoplasmic beta-catenin (encoded by CTNNB1) is stabilized, enabling downstream transcriptional activation by members of the LEF/TCF family. One of the target genes for beta-catenin/TCF encodes c-MYC, explaining why constitutive activation of the WNT pathway can lead to cancer, particularly in the colon. Most colon cancers arise from mutations in the gene encoding adenomatous polyposis coli (APC), a protein required for ubiquitin-mediated degradation of beta-catenin, but a small percentage of colon and some other cancers harbour beta-catenin-stabilizing mutations. Recently, we discovered that transgenic mice expressing an activated beta-catenin are predisposed to developing skin tumours resembling pilomatricomas. Given that the skin of these adult mice also exhibits signs of de novo hair-follicle morphogenesis, we wondered whether human pilomatricomas might originate from hair matrix cells and whether they might possess beta-catenin-stabilizing mutations. Here, we explore the cell origin and aetiology of this common human skin tumour. We found nuclear LEF-1 in the dividing tumour cells, providing biochemical evidence that pilomatricomas are derived from hair matrix cells. At least 75% of these tumours possess mutations affecting the amino-terminal segment, normally involved in phosphorylation-dependent, ubiquitin-mediated degradation of the protein. This percentage of CTNNB1 mutations is greater than in all other human tumours examined thus far, and directly implicates beta-catenin/LEF misregulation as the major cause of hair matrix cell tumorigenesis in humans.
authors: Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, The University of Chicago, Illinois 60637, USA.
authors: E F
authors: EF
authors: Chan
authors: U
authors: U
authors: Gat
authors: J M
authors: JM
authors: McNiff
authors: E
authors: E
authors: Fuchs
mesh_terms: D000595:Amino Acid Sequence; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics; D005787:Gene Frequency; D006201:Hair Diseases / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D008969:Molecular Sequence Data; D009154:Mutation; D018296:Pilomatrixoma / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D015534:Trans-Activators; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D015252:Deoxyribonucleases, Type II Site-Specific; C032229:GANTC-specific type II deoxyribonucleases