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 cells and the cascade of biochemical changes associated with growth have not yet been fully determined. Equally undetermined is an understanding of the mechanism(s) by which tamoxifen blocks estrogen-regulated growth. This study, therefore, attempts to define and correlate the physiological processes in the rat uterus following estrogen and tamoxifen administration with temporal events manifested by mRNA expression of protooncogenes (m-myc, c-ras, c-fos, c-jun), growth factors and/or inhibins (IGF-1, IGF-2, IGF-2 Exon 1 and Exon 2), EGF, TGFB-1, -2, -3), growth factor or inhibin receptors (EGFr, TGFB-2r, TGFB-3r), and estrogen-induced differentiative proteins including estrogen receptor (ER), progesterone receptor (PR). In this study, mRNA was isolated from hormone and antagonist-treated rat uteri at 0', 15', 30', 1 h, 6 h, 24 h, 48 h and 72 h. Expression studies were analysed by dot/Northern blot hybridization with cDNA or oligonucleotide probes for the RNAs mentioned above. Nuclear runoff transcriptional assays were also performed. Our data suggest that fos, myc, ras and jun protooncogenes were expressed from 15' to 48 h after treatment with either estrogen or tamoxifen. Tamoxifen treatment resulted in diminished expression, but incomplete inhibition of the protooncogene mRNAs. Estrogen treatment resulted in rapid elevation of both EGF and EGFr mRNA levels, both of which were suppressed after tamoxifen treatment. Tamoxifen may exert its antiestrogenic effects by inhibiting EGF and EGFr, and myc protooncogene activity on the one hand, and by overexpression of the TGFB isotypes and their receptors on the other hand. With the proliferation cycle short circuited, tamoxifen-treated cells hypertrophied and differentiated to terminal cells by 24-48 h. Working hypotheses for the mechanisms of action of estrogen and tamoxifen are presented based on our data.
Department of Biology, Howard University, Washington, D.C. 20059.
N
N
Bhattacharyya
R
R
Ramsammy
E
E
Eatman
V W
VW
Hollis
W A
WA
Anderson
D000818:Animals; D015152:Blotting, Northern; D002455:Cell Division; D004247:DNA / Q000032:analysis / Q000235:genetics; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006133:Growth Substances / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015345:Oligonucleotide Probes; D011519:Proto-Oncogenes / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D011980:Receptors, Progesterone / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors; D014599:Uterus / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
D004967:Estrogens; D006133:Growth Substances; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D017978:Receptors, Growth Factor; D011980:Receptors, Progesterone; D013629:Tamoxifen; D004247:DNA