PROTOONCOGENE, GROWTH-FACTOR, GROWTH-FACTOR RECEPTOR, AND ESTROGEN AND PROGESTERONE-RECEPTOR GENE-EXPRESSION IN THE IMMATURE RAT UTERUS AFTER TREATMENT WITH ESTROGEN AND TAMOXIFEN

The mechanism(s) by which estrogen regulates cell growth in target cel ls and the cascade of biochemical changes associated with growth have not yet been fully determined. Equally undetermined is an understandin g of the mechanism(s) by which tamoxifen blocks estrogen-regulated gro wth. This study, therefore, attempts to define and correlate the physi ological processes in the rat uterus following estrogen and tamoxifen administration with temporal events manifested by mRNA expression of p rotooncogenes (m-myc, c-ras, c;fos, c-jun), growth factors and/or inhi bins (IGF-1, IGF-2, IGF-2 Exon 1 and Exon 2), EGF, TGFB-1, -2, -3), gr owth factor or inhibin receptors (EGFr, TGFB-2r, TGFB-3r), and estroge n-induced differentiative proteins including estrogen receptor (ER), p rogesterone receptor (PR). In this study, mRNA was isolated from hormo ne and antagonist-treated rat uteri at 0', 15', 30', 1 h, 6 h, 24 h, 4 8 h and 72 h. Expression studies were analysed by dot/Northern blot hy bridization with cDNA or oligonucleotide probes for the RNAs mentioned above. Nuclear runoff transcriptional assays were also performed. Our data suggest that Jos, myc, ras and jun protooncogenes were expressed from 15' to 48 h after treatment with either estrogen or tamoxifen. T amoxifen treatment resulted in diminished expression, but incomplete i nhibition of the protooncogene mRNAs. Estrogen treatment resulted in r apid elevation of both EGF and EGFr mRNA levels, both of which were su ppressed after tamoxifen treatment. Tamoxifen may exert its antiestrog enic effects by inhibiting EGF and EGFr, and myc protooncogene activit y on the one hand, and by overexpression of the TGFB isotypes and thei r receptors on the other hand. With the proliferation cycle short circ uited, tamoxifen-treated cells hypertrophied and differentiated to ter minal cells by 24-48 h. Working hypotheses for the mechanisms of actio n of estrogen and tamoxifen are presented based on our data.