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Patients with dominantly inherited Li-Fraumeni syndrome have a loss-of-function mutation in TP53 and develop diverse mesenchymal and epithelial neoplasms at multiple sites. Trp53 +/- female mice with the BALB/c background provide unique characteristics for the study of breast cancer in Li-Fraumeni syndrome; however, we previously found that female C3H-Trp53+/ - mice did not spontaneously develop mammary tumors. Therefore, we obtained F1 and N2-N4 female mice by backcrossing the BALB/c strain and examined the incidence of mammary and other tumors in lifetime studies. Malignant lymphomas, osteosarcomas, and uterine adenocarcinomas spontaneously developed in approximately 20% or more of Trp53+/ - mice with the C3H background. In contrast, the incidence of uterine adenocarcinomas showed a tendency to decrease, while that of mammary adenocarcinomas gradually increased in mice with the BALB/c strain backcross. Wild-type BALB/c female mice are predisposed to a wide spectrum of neoplasms, including mammary tumors, partly due to genetic factors, whereas uterine tumors are uncommon not only in BALB/c mice but also C3H mice. Thus, genetic factors appear to contribute to a strain-specific predisposition to malignant neoplasms in Trp53+/- mice, and further studies are needed to clarify the detailed mechanisms.

The present study was undertaken to examine the susceptibility of catechol on the gastric mucosa of male rasH2 mice which have high susceptibility to genotoxic carcinogens. Mice were divided into 4 groups consisting of 7 to 15 per group, and given diets containing catechol at doses of 0, 0.2, 0.4 or 0.8% for 26 weeks. In the pyloric mucosa of the stomach, hyperplasias of gastric mucosa were significantly increased in the groups treated with 0.4% or more catechol, along with increased proliferating cell nuclear antigen (PCNA) positive rates, but no stomach tumors were induced. In the fundic mucosa of the stomach, the incidences of atrophic fundic glands with fewer and atrophic parietal cells were significantly increased in the groups treated with 0.4% or more catechol. In the forestomach, epithelial hyperplasias of the limiting ridge were observed in 5 of 15 mice given 0.8% catechol. These results suggest that rasH2 mice are not susceptible to glandular stomach carcinogenesis induced by catechol, although pyloric epithelial hyperplasias and increased proliferation activity of the pyloric mucosa were induced in rasH2 mice given the higher doses of catechol.

The tumorigenic potential of clofibrate, a peroxisome proliferator, was evaluated in a 26-week bioassay using CB6F1-TgHras2 (rasH2) mice carrying a human prototype c-Ha-ras gene. Clofibrate was administered to rasH2 mice orally by gavage at doses of 0 (vehicle control), 125, 250 or 500 mg/kg/day for 26 weeks. Single i.p. injection of 75 mg/kg methyl nitrosourea (MNU) was given to additional rasH2 group as positive control. CB6F1 non-Tg-rasH2 (non-Tg) mice were given either vehicle or 500 mg/kg of clofibrate. In rasH2 mice receiving clofibrate, hepatocellular adenoma was observed in males; 0 (1/15), 125 (0/15), 250 (3/15), and 500 mg/kg (3/15), but not in females. Although the trend test was positive (p

Expression of glutathione-S-transferase P-form (GST-P) mRNA revealed by in situ hybridization histochemistry was investigated in enzyme altered foci and nodules during rat hepatocarcinogenesis, using diethylnitrosamine initiation followed by 2-acetylaminofluorene promotion protocol. The majority of early foci showed uniformly high levels of GST-P mRNA, however, some lesions after completion of the promotion regimen exhibited a progressive loss of expression of GST-P mRNA. Most of the continuous and strong GST-P mRNA positive lesions were also transforming growth factor-α (TGF-α)-positive lesions, a putative potent mitogen for altered hepatocytes. Moreover, the proliferating cell nuclear antigen (PCNA) index was significantly (p