Differential Response of Estrogen Receptor α and Estrogen Receptor β to Partial Estrogen Agonists/Antagonists

Abstract

The existence of two rather than one estrogen receptor, today characterized as estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), indicates that the mechanism of action of 17beta-estradiol and related synthetic drugs is more complex than previously thought. Because the homology of amino acid residues in the ligand-binding domain (LBD) of ERbeta is high compared with those amino acid residues in ERalpha LBD, previously shown to line the ligand binding cavity or to make direct contacts with ligands, it is not surprising that many ligands have a similar affinity for both receptor subtypes. We report that 17alpha-ethynyl, 17beta-estradiol, for example, has an ERalpha-selective agonist potency and that 16beta,17alpha-epiestriol has an ERbeta-selective agonist potency. We also report that genistein has an ERbeta-selective affinity and potency but an ERalpha-selective efficacy. Furthermore, we show that tamoxifen, 4-OH-tamoxifen, raloxifene, and ICI 164,384 have an ERalpha-selective partial agonist/antagonist function but a pure antagonist effect through ERbeta. In addition, raloxifene displayed an ERalpha-selective antagonist potency, in agreement with its ERalpha-selective affinity. However, although ICI 164,384 showed an ERbeta-selective affinity, it had a similar potency to antagonize the effect of 17beta-estradiol in the ERalpha- and ERbeta-specific reporter cell lines, respectively. In conclusion, our data indicate that the ligand binding cavity of ERbeta is probably more different from that of ERalpha than can be anticipated from the primary sequences of the two ER subtypes and that it will be possible to develop receptor-specific ligands that may form the basis of novel pharmaceuticals with better in vivo efficacy and side effect profile than current available drugs.

The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1

“…In fact, both drugs exhibited a complete antagonist effect on E 2 -mediated stimulation of the FAAH promoter and they did not have any direct effect when given alone. This is in agreement with a previous study reporting that TMX exhibited a pure antagonism in an ERb expressing system [36]. Consistently with these data epiE 2 , which is ineffective at ERs [28,29], had no effect on FAAH expression.…”

“…The biological effects of E 2 are mediated by ERa and ERb [36], and it has been previously demonstrated that mouse Sertoli cells express only ERb [3]. By using a ChIP assay with Sertoli cells, we examined the ligand-dependent recruitment of ERb to the faah promoter in vivo, and we found that E 2 increased ERb binding to ERE2/3 promoter sites.…”

Estrogen receptor β acts as a dominant regulator of estrogen signaling

“…In agreement with previous observations, ERb is poorly activated by E 2 concentrations below 1 nM (Figure 1b) (Barkhem et al, 1998). In contrast, ERa, reaches approximately 50% activation already at 0.01 nM and shows maximal transcriptional activity at 0.1 nM (Figure 1a).…”

“…Previous studies have indicated that the iso¯avonoid genistein shows a higher a nity for ERb (Barkhem et al, 1998;Kuiper et al, 1997). 293 cells were cotransfected as before with the ERE-reporter plasmid and ERa or ERb expressing plasmids and treated with increasing amounts of genistein.…”

Effect of ligand-activated estrogen receptor β on lymphoma growth in vitro and in vivo

“…To more quantitatively determine the selectivity of KB9520 for ERb over ERa, HEK293 cells, genetically engineered to stably express human ERa and ERb, respectively, were used as described previously. 33 The dose-response curves showed an EC 50 value of 6.7 nM for KB9520 in the HEK293-ERb cells and B4.9 mM for ERa in the HEK293-ERa cells, that is, KB9520 is a highly ERbselective agonist with approximately 700-fold selectivity for ERb over ERa (Supplementary Figure 2C). To test the antiproliferative effect of activated ERb, EG7, Raji and Ramos cells were treated with either E 2 , selective ERa agonist PPT or selective ERb agonists KB9520 or DPN in culture.…”