| Estrogens are involved in the proliferation of breast cancer cells. Because of this, many selective estrogen receptor modulators (SERMs), once known as estrogen receptor (ER) antagonists, have been developed. The old SERM, tamoxifen shows ER antagonist activities in the breast cancer cell growth, but it acts as an ER agonist in the endometrium thereby increasing the risk of endometrial cancer. Therefore, two newly developed SERMs, GW 5638 (GW) and EM 800 (EM) were attractive to us due to their ER antagonist activities in uteri and breast cancer cells.; We have used the sheep uterus as a model to study 4-OH-tamoxifen (Tam), GW and EM effects on the expression of estrogen receptor-α (ER) and progesterone receptor (PR), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and cyclophilin (CYC) genes, which are up-regulated by estradiol (E2) treatment in sheep uterus. GW exhibited fewer agonist effects than Tam, while EM demonstrated the greatest antagonism of E2-induced levels of ER, PR and CYC gene expression in endometrium. These SERMs also regulated ER, PR and CYC gene expression in myometrium with gene- and cell layer-specificity.; We determined the effects of sheep endometrial explant culture: down-regulation of ER and PR, and up-regulation of GAPDH mRNA levels. However, E2 treatment in vitro prevented the decreases in PR gene expression, but not that of ER. EM also decreased ER and PR mRNA levels in endometrial explants: indicating ex vivo response of the tissue. Similar to E2 effect, EM stabilized ER mRNA in explants.; The effects of these SERMs (Tam, ICI 182, 780 and GW) on ER and PR gene expression were investigated in three endometrial cell lines. All SERMs antagonized E2-induced PR mRNA levels, but not that of ER. E2 increased ER mRNA levels in sheep endometrial stromal cells without changing ER mRNA stability, but it decreased ER mRNA levels with destabilizing ER mRNA in ECC-1 cells.; The results suggest that new SERMs show the mixed ER agonist/antagonist effects depending upon cell and gene examined. New SERMs display more ER antagonist activities and fewer ER agonist activities than Tam does in endometrium. |
