2-difluoromethylornithine and dehydroepiandrosterone inhibit mammary tumorprogression but not mammary or prostate tumor initiation in C3(1)/SV40 T/t-antigen transgenic mice

Female transgenic mice that express SV40 T/t antigens under the regulatory control of the rat C3(1) gene spontaneously develop multifocal Mammary lesi ons that predictably evolve into invasive, hormone-independent carcinomas, whereas male mice are prone to develop prostate cancer. Chemo-preventive ag ents were administered to female C3(1)/SV40 large T-antigen mice from 7 to 19 weeks of age, during which time the mammary lesions developed and progre ssed to invasive carcinomas. No significant differences in the numbers of p reinvasive mammary intraepithelial neoplasia lesions (histologically simila r to human ductal carcinoma in situ) were observed after 2 or 8 weeks of tr eatment between mice receiving either vehicle alone, dehydroepiandrosterone (DHE A), or 2-difluoromethylornithine (DFMO). However, a dose-response red uction in invasive carcinoma growth was observed for both DFMO, an inhibito r of ornithine decarboxylase, and DHEA, the primary steroid precursor to bo th androgens and estrogens in primates. Despite unaltered expression of the transgene, tumor incidence was reduced approximately 20% by DFMO (8000 mg/ kg) and 30% by DHEA (4000 mg/kg; P < 0.05). Tumor multiplicity was reduced by similar to 50% by both DFMO and DHEA (P < 0.05). DFMO had a dose-depende nt effect on total tumor burden, which was reduced by 25% at low doses 4000 mg/kg) and 70% at high doses (8000 mg/kg). DHE A reduced tumor burden by 5 0% and 66% at low (2000 mg(kg) and high (4000 mg/kg) doses, respectively. I nterestingly, despite its inhibitory effects on tumor development, DHEA cau sed a dose-dependent increase of serum estradiol levels that we have previo usly shown to increase mammary tumor formation in this model. No effect on the development of the prostate cancer precursor lesions (prostate intraepi thelial neoplasia) was observed when mice were treated with DHEA, DFMO, toc opherol acetate, selenomethionine, or 9-cis-retinoic acid, although the eff ects on late-stage prostate cancer development were not determined. These r esults demonstrate that despite the expression of the highly transforming C 3(1)/SV40 large T-antigen transgene, this transgenic model can be used to s tudy the effects of chemopreventive agents on mammary cancer progression. T he tumor-inhibitory effects of DHEA and DFMO on mammary cancer growth appea r to occur after the development of preinvasive lesions, suggesting that th ese agents inhibit tumor progression but not initiation.