Antiestrogens antagonize the stimulatory effect of epidermal growth factor on the induction of progesterone receptor in fetal uterine cells in culture.

In fetal uterine cells in culture, epidermal growth factor (EGF) increased progesterone receptor concentrations more than 2-fold. Two other growth factors, transforming growth factor-alpha and fibroblast growth factor, were not able to cause the same increase. This response to EGF was dose dependent; a half-maximal effect was obtained at 10(-10) M. The antiestrogens tamoxifen and 4-hydroxytamoxifen were able to antagonize the stimulatory effect of EGF on progesterone receptor concentrations, but they did not affect its mitogenic effect. The inhibitory effect of 4-hydroxytamoxifen depended on concentration; half-maximal inhibition was observed between 0.5-1 X 10(-9) M. 4-Hydroxytamoxifen could completely inhibit the progesterone receptor increase due to EGF even when added to cells already exposed to the growth factor for 6 days. EGF seems to be acting as an estrogen in increasing progesterone receptors in fetal uterine cells, and antiestrogens are potent antagonists of this response, indicating that growth factors may also be involved in some protein-inducing effects of estrogens. Since estrogen receptor levels were at the limits of detectability under all of the experimental conditions studied, nonestrogen receptor-mediated pathways may be involved. These observations show the potential importance of other factors acting in combination with estrogens in the modulation of progesterone receptor levels.