A common human skin tumour is caused by activating mutations in β-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.
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β-catenin, a critical mediator of the WNT signaling pathway, plays an important role in tumorigenesis.
“β-catenin, a critical mediator of the WNT signaling pathway, plays an important role in tumorigenesis.441–444”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [443]
When WNT ligands are present, β-catenin degradation is impeded, causing its nuclear translocation and subsequent binding to T-cell factor (TCF), which results in the transcriptional activation of their target genes.
“When WNT ligands are present, β-catenin degradation is impeded, causing its nuclear translocation and subsequent binding to T-cell factor (TCF), which results in the transcriptional activation of their target genes.443,445,446”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [443]
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- Authors
- Chan, E., Gat, U., McNiff, J. M., & Fuchs, E.
- Affiliations
- Howard Hughes Medical Institute (US)
- Yale University (US)
- Corresponding author
- Fuchs, Elaine
- Venue
- Nature Genetics
- Published
- 1999-04
- Volume
- 21
- Issue
- 4
- Pages
- 410-413
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- DOI
- 10.1038/7747
- OpenAlex
- W1484268538
- Cited by
- 612
- References
- 31
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 7 · 2023: 13 · 2022: 12 · 2021: 9 · 2020: 19 · 2019: 12 · 2018: 10 · 2017: 20 · 2016: 18 · 2015: 14 · 2014: 26 · 2013: 24 · 2012: 27
- FWCI
- 15.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH-RO1-AR31737, R01AR031737)
- National Institute of Dental and Craniofacial Research (NCI-P50DE/CA-11921)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Dermatology › Cancer and Skin Lesions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- pilomatrixoma, β-catenin, CTNNB1 mutation, Wnt signaling, LEF1, hair matrix cells, skin tumours, tumor cell of origin, hair follicle morphogenesis, transgenic mice, c-Myc, APC, carcinogenesis
- MeSH terms
- Amino Acid Sequence, Cytoskeletal Proteins, DNA-Binding Proteins, Gene Frequency, Hair Diseases, Humans, Molecular Sequence Data, Mutation, Skin Neoplasms, Transcription Factors, Deoxyribonucleases, Type II Site-Specific, Trans-Activators, Polymerase Chain Reaction, Sequence Analysis, DNA, Pilomatrixoma, beta Catenin, Lymphoid Enhancer-Binding Factor 1
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