EFFECT OF THE VIABLE-YELLOW (A(VY)) AGOUTI ALLELE ON SKIN TUMORIGENESIS AND HUMORAL HYPERCALCEMIA IN V-HA-RAS TRANSGENIC TG.AC MICE

We previously reported that papillomas can arise from the follicular e pithelium of v-Ha-ras transgenic TG.AC mice. Since the viable-yellow m utation (A(vy)) Of the mouse agouti gene which regulates coat color pi gmentation by acting within the micro-environment of the hair follicle has been shown to function as a tumor promoter in the liver, we hypot hesized that it may also play a role in TG.AC skin tumorigenesis. Endo genous agouti protein product was detected in the outer root sheath of anagen hair follicles following plucking of the hair shaft, but not i n the interfollicular epithelium, in TG.AC mice on an FVB/N genetic ba ckground. It was also detected in papillomas from these mice produced by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment or plucking. E xpression of the A(vy) allele in the v-Ha-ms transgenic TG.AC mouse li ne results in an similar to 2-fold increase in papilloma development c ompared with controls which did not carry the A(vy) allele following t wice-weekly treatment with 1.25, 2.5 or 5.0 mu g TPA. In addition, TPA -treated, papilloma-bearing F-1 mice which carried the A(vy) allele, b ut not F-1 mice which did not carry the A(vy) allele, exhibited a synd rome of humoral hypercalcemia mediated by parathyroid hormone-related protein (PTHrP) that led to weight loss, hypercalcemia and hypophospha temia, Thus, we conclude that the A(vy) allele can influence the devel opment of skin tumors and PTHrP-mediated humoral hypercalcemia in v-Ha -ras transgenic TG.AC mice.