TAMOXIFEN STIMULATES EXPRESSION OF THE C-FOS PROTOONCOGENE IN RODENT UTERUS

Estrogens regulate the in vivo expression of the c-fos protooncogene i n rat uterus, and this regulation appears to occur at the transcriptio nal level. This system thus provides the ability to study the in vivo effects of antiestrogens on specific gene expression in normal estroge n target tissue. Immature rats were treated with estradiol, tamoxifen, or other nonsteroidal antiestrogens, total uterine RNA was isolated, and c-fos transcript levels were monitored by blot analysis. Tamoxifen increases the 2.2-kilobase c-fos transcript approximately 20-fold in 6 hr. This effect is comparable in magnitude to that produced by estra diol, but the maximum response to the hormone occurs in 3 hr. c-fos in duction is observed at doses of 0.1-10 mg/kg tamoxifen. The nonsteroid al antiestrogens nafoxidine, Cl-628, and 4-hydroxy-tamoxifen also indu ce c-fos expression. The induction of c-fos by both estradiol and tamo xifen is blocked by the progestin medroxyprogesterone acetate. In addi tion to effects on c-fos mRNA, tamoxifen also increases uterine levels of c-jun, jun-B, and c-myc mRNAs. These results indicate that tamoxif en acts in vivo as an estrogen agonist for activating expression of ce llular oncogenes in normal uterine tissue.