Early p53-positive foci as indicators of tumor risk in ultraviolet-exposedhairless mice: Kinetics of induction, effects of DNA repair deficiency, and p53 heterozygosity

p53 mutations appear to be early events in skin carcinogenesis induced by c hronic UVB irradiation. Clusters of epidermal cells that express p53 in mut ant conformation ("p53 positive foci") are easily detected by immunohistoch emical staining long before the appearance of skin carcinomas or their prec ursor lesions, In a hairless mouse model, we determined the dose-time depen dency of the induction of these p53+ loci and investigated the relationship with the induction of skin carcinomas. The density of p53+ foci may be a g ood direct indicator of tumor risk. Hairless SKH1 mice were exposed to either of two regimens of daily UVB (500 or 250 J/m(2) broadband UV from Philips TL12 lamps: 54% UVB 280-315 nm), W ith the high-dose regimen, the average number of p53+ foci in a dorsal skin area (7.2 cm(2)) increased rapidly from 9.0 +/- 2.1 (SE) at 15 days to 470 +/- 80 (SE) at 40 days. At half that daily dose, the induction of p53+ foc i was slower by a factor of 1.49 +/- 0.15, very similar to a previously obs erved slower induction of squamous cell carcinomas by a factor of 1.54 +/- 0.02, In a double-log plot of the average number of p53+ loci versus time, the curves for the two exposure regimens ran parallel (slope, 3.7 +/- 0.7), similar to the curves for the number of tumors versus time (slope, 6.9 +/- 0.8). The difference in slopes (3.7 versus 6.9) is in line with the conten tion that more rate-limiting steps are needed to develop a tumor than a p53 + focus. By the time the first tumors appear (around 7-8 weeks with the hig h daily dose), the dorsal skin contains >100 p53+ foci/cm(2), To further validate the density of p53+ loci as a direct measure of tnmor r isk, we carried out experiments with transgenic mice with an enhanced susce ptibility to UV carcinogenesis, homozygous Xpa knockout mice (deficient in nucleotide excision repair) and heterozygous p53 knockout mice (i.a. partia lly deficient in apoptosis), In both of these cancer-prone strains, the p53 + loci were induced at markedly increased rates, corresponding to increased rates of carcinoma formation. Therefore, the frequency of p53+ loci appear s to correlate well with UVB-induced tumor risk.