A common human skin tumour is caused by activating mutations in beta-catenin

Nat Genet. 1999 Apr;21(4):410-3. doi: 10.1038/7747.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Cytoskeletal Proteins / genetics*
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / metabolism
  • Deoxyribonucleases, Type II Site-Specific / genetics
  • Gene Frequency
  • Hair Diseases / genetics*
  • Hair Diseases / pathology
  • Humans
  • Lymphoid Enhancer-Binding Factor 1
  • Molecular Sequence Data
  • Mutation*
  • Pilomatrixoma / genetics*
  • Pilomatrixoma / pathology
  • Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Trans-Activators*
  • Transcription Factors / analysis
  • Transcription Factors / metabolism
  • beta Catenin


  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • Trans-Activators
  • Transcription Factors
  • beta Catenin
  • Deoxyribonucleases, Type II Site-Specific
  • GANTC-specific type II deoxyribonucleases