β-carotene pails to act as a tumor promoter, induces RAR expression, and prevents carcinoma formation in a two-stage model of skin carcinogenesis in male Sencar mice

Clinical trials have shown a significant increase in incidence of lung cancer among smokers and asbestos workers supplemented with beta-carotene, suggesting a tumor-promoting activity for this agent We set out to test possible tumor-promoting and chemoprerentive activities of dietary and topical beta-carotene in the two-stage 7,12-dimethylbenz[a]anthracene-12-O-tetradecanoylphorbol 13-acetate (TPA) model of mouse skin carcinogenesis. In the first study, the effects of three levels of dietary beta-carotene (6, 60, and 600 mu g/g purified diet containing no other retinoid or carotenoid) were assessed over a period of 42 weeks. Carcinoma yield was reduced by similar to 50% in the 600 mu g/g diet group (mean 0.22 carcinomas/mouse) compared with the 6 mu g/g diet group (mean 0.44 carcinomas/mouse, p = 0003). The 60 mu g/g diet group showed a pattern of inhibition similar to the 600 mu g/g diet group. A protective effect (25% reduction) of beta-carotene (in the 600 mu g/g diet group) on papilloma formation was also found. However, the intermediate 60 mu g/g diet group showed the same incidence as the low 6 mu g/g diet group. This points to a lack of correlation between papilloma and carcinoma incidence, as we also found in previous work on dietary retinoids and carotenoids. The purpose of the second study was to assess whether topical beta-carotene (2 mu g) has hrmor-promoting or chemopreventive activity in the two-stage protocol. In the absence of TPA, beta-carotene had no significant tumor-promoting activity. Instead, papilloma yield induced by TPA was decreased by topical beta-carotene om an average of 20 to similar to 10 papillomas/mouse (p = 2.5 x 10(-7)). The effect of topical p-carotene persisted beyond the treatment period (Week 24) until the termination of the study at Week 42. Western blot analysis of mouse skin extracts showed that topical beta-carotene upregulated retinoic acid receptor-alpha and -gamma expression in the dorsal skin. This finding suggests that beta-carotene may work as a chemopreventive agent by upregulating the expression of retinoid receptors in mouse skin. In conclusion, our data show that beta-carotene prevents skin carcinoma formation, induces retinoic acid receptor expression, and fails to act as a tumor promoter in the two-stage model of skin tumorigenesis.