THE ANTIESTROGEN TAMOXIFEN INDUCES C-FOS AND JUN-B, BUT NOT C-JUN OR JUN-D, PROTOONCOGENES IN THE RAT UTERUS

Tamoxifen is the leading therapeutic agent in the management of breast cancer. Although classified as an antiestrogen, tamoxifen displays partial estrogen agonist activity in the rat uterus. The molecular mechanism of the uterotrophic action of tamoxifen is unclear. The purpose of the present study was to investigate the effect of tamoxifen on activation of the c-fos, c-jun, jun-B and jun-D protooncogenes in rat uteri in vivo. These immediate early response genes are transcription regulatory factors that can regulate the expression of genes containing an AP-1 recognition site. Northern blotting analysis of total uterine RNA revealed that treatment of adult, ovariectomized rats with tamoxifen elevated levels of c-fos mRNA 2.4-, 5.3- and 6.2-fold over expression in untreated rats by 6, 12 and 24 h post-tamoxifen injection, respectively. Tamoxifen induction of c-fos was still apparent by 48 h post injection. The effect of tamoxifen on expression of the jun gene family was also examined. Tamoxifen markedly induced uterine expression of jun-B mRNA by approximately 10-fold over expression in untreated rats by 24 h after administration. By 48 h, levels of jun-B transcripts had declined to 2.3 fold over control values. In contrast, only slight induction of c-jun and jun-D expression (1.3- and 1.6-fold, respectively) by 12 h after tamoxifen treatment was observed. The kinetic pattern of tamoxifen-induced expression of these genes was strikingly different from what has been reported for other stimuli, e.g., estrogen. This is the first report to examine the effects of tamoxifen on protooncogene expression in the rat uterus. Our results indicate that the activation of immediate early response genes may play a role in the uterotrophic actions of tamoxifen. However, based on the kinetics of induction, we suggest that tamoxifen is much less effective at transciptional activation of protooncogenes than other uterine agonists, e.g., estrogen. The lack of synchronous expression of the jun genes may indicate that distinct control mechanisms exist among members of this protooncogene family.