Inhibitory effect of genistein on a tumor promoter-induced c-fos and c-jun expression in mouse skin

The effects of genistein, a soybean isoflavone, on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced expression of c-fos and c-jun in CD-1 mouse skin have been investigated. A promoting dose (8.5 mu mol) of TPA significantly increases transcript levels of c-fos, and 2.7 and 3.2 kb c-jun mRNA in mouse skin by 7.0-, 3.2-, and 1.7-fold, respectively. Topical application of genistein 30 min before TPA treatment inhibits TPA-induced expression of these protooncogenes. Suppression of c-fos was more pronounced than that of c-jun, and at a dose of 10 mu mol genistein, TPA-induced c-fos expression was almost completely diminished. Genistein exhibited only a weak suppressive effect on TPA-induced c-jun mRNA expression. Effect of application time of genistein on TPA-induced c-fos expression was also investigated. The results showed that topical application of 10 mu mol genistein 30 min prior to, simultaneously, and 30 min after tumor promoter treatment can equally suppress TPA-induced c-fos expression. The mechanism by which genistein inhibits TPA-induced proto-oncogene expression is unknown. However, it appears that the inhibition of c-fos expression by genistein is independent of the protein kinase C (PKC) activation pathway because of its weak suppressive effect on PKC activity. It is hypothesized that the inhibitory effect of genistein on TPA-induced c-fos expression may be through the modulation of mitogen-activated protein (MAP) kinase in vivo.