The Tg.AC Transgenic Mouse as a Screening Tool for Anticarcinogens: Broccoli Juice Protected Against 12-O-Tetradecanoylphorbol-13-Acetate (TPA) But Not Benzo[a]Pyrene (B[a]P)-Induced Skin Tumors

Abstract

The Tg.AC mouse model was used to assess the utility of a short-term screening assay to evaluate compounds with suspected carcinogenic/anticarcinogenic activity. Crude broccoli juice (BROC) was evaluated for antitumorigenic effects against 12-Otetradecanoylphorbol-13-acetate (TPA) and benzo[a]pyrene (B[a]P)-induced tumors. Groups of female mice were dosed three times a week (200 μL/mouse) with one of the following: acetone vehicle control, TPA (2.5 μg/mouse), B[a]P (250 μg/mouse), BROC/TPA, or BROC/B[a]P. BROC (200 μL, 1:1 acetone) was dermally administered 1 h prior to the administration of either TPA or B[a]P to evaluate anticarcinogenic activity. Papilloma numbers were recorded weekly for each mouse. Following 13 weeks of treatment, samples from the dermal test site from all mice were examined histologically. B[a]P-induced tumors were evaluated for transgene expression by RT-PCR and immunohistochemically for cyclin D1 and p53 proteins. TPA and B[a]P induced tumors in all surviving mice. BROC showed effective antitumorigenic activity against TPA but not B[a]P. Tumor development was distinct between TPA (small, benign papillomas) and B[a]P (large, ulcerated, squamous cell carcinomas). The transgene v-Ha-ras, cyclin D1, and p53 proteins were highly expressed in B[a]P tumors where progression to malignancy was rapid (< 13 weeks). The effects induced by B[a]P appeared to cooperate with transgene expression to enhance conversion to malignancy and could serve as a phenotypic indicator for genotoxic versus nongenotoxic carcinogens. The model distinguished differences in tumor response for carcinogenic and anticarcinogenic agents. The Tg.AC mouse model offers a potentially useful screen for identifying new anticarcinogenic agents and directing future mechanistic evaluations.