Ultraviolet B radiation-induced skin cancer in mice defective in the Xpc, Trp53, and Apex (HAP1) genes: Genotype-specific effects on cancer predisposition and pathology of tumors

David L. Cheo, Lisiane B. Meira, Dennis K. Burns, Antonio M. Reis, Tony Issac, Errol C. Friedberg

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Mutations in nucleotide excision repair (NER) genes in humans result in the UV-induced skin cancer-prone disease xeroderma pigmentosum (XP). Mouse models that mimic XP have provided an informative experimental system with which to study DNA repair, as well as the molecular pathology of UV radiation-induced skin cancer. We reported previously that mice defective in the Xpc gene (Xpc(-/-)) are highly predisposed to UVB radiation-induced skin cancer and that the appearance of skin cancer is more rapid in Xpc Trp53 double mutants. Extended studies now demonstrate an increased predisposition to UVB radiation-induced skin cancers in Xpc heterozygous mice compared with normal mice. We also show that Xpc Trp53 double heterozygous mutants are more predisposed to skin cancer than Trp53 single heterozygous mice. No mutations were detected in the cDNA of the remaining Xpc allele, suggesting that haploinsufficiency of the Xpc gene may be operating and is a risk factor for UVB radiation-induced skin cancer in mice. Skin tumors from Xpc(-/-) mice were exclusively well or moderately well-differentiated squamous cell carcinomas. In Xpc(+/+) and Xpc(+/-) mice, many of the squamous cell carcinomas were less well differentiated. We also documented previously increased predisposition to UV radiation-induced skin cancers in Xpc(-/-) Apex(+/-) mice. Here we show the absence of mutations in the cDNA of the remaining Apex allele, a further suggestive indication of haploinsufficiency and its resulting predisposition to skin cancer. The Trp53 and Apex heterozygous conditions altered the skin tumor spectrum to more poorly differentiated forms in all Xpc genotypes.

Original languageEnglish (US)
Pages (from-to)1580-1584
Number of pages5
JournalCancer research
Volume60
Issue number6
StatePublished - Mar 15 2000

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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