The molecular basis of tamoxifen induction of mouse uterine epithelial cell proliferation.
Tamoxifen, a selective estrogen modulator (SERM) that has found clinical utility in the treatment of breast cancer, is an antagonist in the breast and an agonist in the uterus. These agonist actions in the uterus lead to an increased risk of endometrial cancer. In this study in mice we have analyzed the mechanism of action of tamoxifen in inducing cell proliferation in the uterine luminal epithelia. Tamoxifen induces a wave of DNA synthesis in these epithelial cells with kinetics similar to those seen after 17beta-estradiol (E(2)) treatment. However, by these criteria of mitogenicity, it is much less potent and never achieves full estrogenicity. This uterine epithelial cell proliferation is preceded by the mobilization of cyclin D1 from the cytoplasm to the nucleus which, together with CDK4, phosphorylates members of the Rb-retinoblastoma family of proteins, pRb and p107. Subsequent to this initial nuclear accumulation of cyclin D1, cyclin E and then cyclin A are induced that, together with the activation of CDK2, results in enhanced cyclin E- and cyclin A-dependent CDK2 kinase activity and further phosphorylation of pRb and p107. These actions of tamoxifen parallel those of E(2). Tamoxifen also induced the classical estrogen water imbibition response. However, in this it was more potent, producing a maximal response at doses that do not affect DNA synthesis. This suggests that the uterotropic response is not an accurate predictor of the compound's hyperplasia responses. We can conclude that, in its effects on proliferation, tamoxifen acts as a classical impeded estrogen and this suggests that the AF-1 transcription activation domain of the estrogen receptor that is activated upon both E(2) and tamoxifen binding to this receptor regulates these responses in the uterus.
Zhang
Haifan
H
Center for the Study for Reproductive Biology and Women's Health, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
McElrath
Tim
T
Tong
Wei
W
Pollard
Jeffrey W
JW
D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D019925:Cyclin A / Q000032:analysis; D019938:Cyclin D1 / Q000032:analysis; D019927:Cyclin E / Q000032:analysis; D051357:Cyclin-Dependent Kinase 2; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008815:Mice, Inbred Strains; D010766:Phosphorylation; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D014599:Uterus / Q000166:cytology* / Q000187:drug effects
D019925:Cyclin A; D019927:Cyclin E; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D019938:Cyclin D1; D004247:DNA; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2