Journal
ONCOGENE
Volume 24, Issue 47, Pages 7055-7063Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1208863
Keywords
UVB carcinogenesis; p53; tumor progression; differentiation; skin tumor
Funding
- NCI NIH HHS [CA 46523, CA 16672, U01 CA105345] Funding Source: Medline
- NIEHS NIH HHS [ES07784] Funding Source: Medline
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Chronic exposure to ultraviolet (UV) radiation causes skin cancer in humans and mice. We have previously shown that in hairless SKH-hr1 mice, UVB-induced p53 mutations arise very early, well before tumor development. In this study, we investigated whether discontinuation of UVB exposure before the onset of skin tumors results in the disappearance of p53 mutations in the skin of hairless SKH-hr1 mice. Irradiation of mice at a dose of 2.5 kJ/m(2) three times a week for 8 weeks induced p53 mutations in the epidermal keratinocytes of 100% of the mice. UVB irradiation was discontinued after 8 weeks, but p53 mutations at most hotspot codons were still present even 22 weeks later. During that period, the percent of mice carrying p53(V154A/R155C), p53(H175H/H176Y), and p53(R275C) mutant alleles remained at or near 100%, whereas the percentage of mice with p53(R270C) mutation decreased by 45%. As expected, discontinuation of UVB after 8 weeks resulted in a delay in tumor development. A 100% of tumors carried p53(V154A/R155C) mutant alleles, 76% carried p53(H175H/H176Y) mutants, and 24 and 19% carried p53(R270C) and p53(R275C) mutants, respectively. These results suggest that different UVB-induced p53 mutants may provide different survival advantages to keratinocytes in the absence of further UVB exposure and that skin cancer development can be delayed but not prevented by avoidance of further exposure to UVB radiation.
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