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 pa rtial estrogen agonist activity in the rat uterus. The molecular mecha nism of the uterotrophic action of tamoxifen is unclear. The purpose o f the present study was to investigate the effect of tamoxifen on acti vation of the c-fos, c-jun, jun-B and jun-D protooncogenes in rat uter i in vivo. These immediate early response genes are transcription regu latory factors that can regulate the expression of genes containing an AP-1 recognition site. Northern blotting analysis of total uterine RN A 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, respect ively. Tamoxifen induction of c-fos was still apparent by 48 h post in jection. The effect of tamoxifen on expression of the jun gene family was also examined. Tamoxifen markedly induced uterine expression of ju n-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 d eclined to 2.3 fold over control values. In contrast, only slight indu ction 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 activatio n of immediate early response genes may play a role in the uterotrophi c actions of tamoxifen. However, based on the kinetics of induction, w e suggest that tamoxifen is much less effective at transciptional acti vation 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.