TRIPHENYLETHYLENE ANTIESTROGENS INDUCE UTERINE VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION VIA THEIR PARTIAL ESTROGEN AGONIST ACTIVITY

Estradiol induces vascular endothelial growth factor (VEGF) expression in the rat uterus and this may contribute to the hyperemia and increa sed vascularity produced by estrogens in this target tissue. Triphenyl ethylene antiestrogens such as tamoxifen have mixed agonist/antagonist activity and their specific effects are tissue and gene specific. The se drugs exhibit primarily antiestrogenic actions in mammary tissue an d are thus used for the treatment of breast cancer. These drugs are al so suggested to be inhibitors of angiogenesis. However, uterine side e ffects of tamoxifen are thought to stem largely from the agonist activ ity of the drug in this tissue. Since side effects of tamoxifen such a s uterine bleeding and endometrial cancer seem likely to have an angio genic component, we have examined the effects of this drug, its metabo lite, 4-hydroxy-tamoxifen and two additional triphenylethylene antiest rogens, nafoxidine and clomiphene, on the expression of VEGF and anoth er estrogen regulated gene, c-Sos, using the rat uterus as an experime ntal system. All four compounds increase uterine VEGF and c-fos mRNA l evels indicating that the triphenylethylene class of antiestrogens are predominantly agonists for the induction of these genes in the uterus . (C) 1997 Elsevier Science Ireland Ltd.