Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke

Background: Epidemiologic studies have demonstrated that individuals who ea t more fruits and vegetables and/or have high levels of serum beta-carotene have a lower risk of cancer, especially lung cancer. However, recent human intervention studies using beta-carotene supplements have shown an increas e in the risk of lung cancer among smokers and asbestos workers. In this st udy, we used an animal model system to evaluate the hazard associated with a combination of high-dose beta-carotene supplementation and tobacco smokin g. Methods: Ferrets were given a beta-carotene supplement, exposed to cigar ette smoke, or both for 6 months. Cell proliferation and squamous metaplasi a in lung tissue were assessed by examination of proliferating-cell nuclear antigen expression and histopathologic examination, respectively, beta-Car otene and retinoid concentrations in lung tissue and plasma samples were an alyzed by highperformance liquid chromatography, Expression of genes for re tinoic acid receptors (RARs) and activator protein-1 (encoded by the c-Jun and c-Fos genes) in lung tissue specimens was examined by western blotting. Results: A strong proliferative response in lung tissue and squamous metap lasia was observed in all beta-carotene-supplemented animals, and this resp onse was enhanced by exposure to tobacco smoke. When compared with control groups, all three treatment groups had statistically significantly lower co ncentrations of retinoic acid in lung tissue, and they exhibited 18%-73% re ductions in RAR beta gene expression; however, RAR alpha and RAR gamma gene expression was not reduced. Ferrets given a p-carotene supplement and expo sed to tobacco smoke had threefold to fourfold elevated expression of the c -Jun and c-Fos genes. Conclusions: Diminished retinoid signaling, resulting from the suppression of RAR beta gene expression and overexpression of act ivator protein-1, could be a mechanism to enhance lung tumorigenesis after high-dose beta-carotene supplementation and exposure to tobacco smoke.