Nat Genet  1999 Apr;21(4):410-3 

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

Chan EF, Gat U, McNiff JM, Fuchs E.

Howard Hughes Medical Institute, Department of Molecular Genetics and Cell
Biology, The University of Chicago, Illinois 60637, USA.

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.

PMID: 10192393 [PubMed - indexed for MEDLINE]