Tamoxifen stimulates expression of the c-fos proto-oncogene in rodent uterus

Estrogens regulate the in vivo expression of the c-fos proto-oncogene in rat uterus, and this regulation appears to occur at the transcriptional level. This system thus provides the ability to study the in vivo effects of antiestrogens on specific gene expression in normal estrogen 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 estradiol, but the maximum response to the hormone occurs in 3 hr. c-fos induction is observed at doses of 0.1-10 mg/kg tamoxifen. The nonsteroidal antiestrogens nafoxidine, CI-628, and 4-hydroxytamoxifen also induce c-fos expression. The induction of c-fos by both estradiol and tamoxifen is blocked by the progestin medroxyprogesterone acetate. In addition to effects on c-fos mRNA, tamoxifen also increases uterine levels of c-jun, jun-B, and c-myc mRNAs. These results indicate that tamoxifen acts in vivo as an estrogen agonist for activating expression of cellular oncogenes in normal uterine tissue.