Differential SERM activation of the estrogen receptors (ERα and ERβ) at AP-1 sites

Background: The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are triphenylethylene derivatives that affect transcriptional regulation by the estrogen receptors (ERα and ERβ) but show different effects in different tissues. A third triphenylethylene derivative, GW-5638, displays tissue selectivity in rats identical to that of raloxifene, suggesting that GW-5638 and raloxifene share a mechanism of action that is different from that of tamoxifen. Results: Both GW-5638 and its hydroxylated analog GW-7604 were tested for their ability to bind to ERα and ERβ and their ability to affect transcription of ERα and ERβ at a consensus estrogen response element and an ER/AP-1 response element. The drugs were found to have the same affinity for ERα and ERβ, although they were also found to activate transcription from an AP-1 promoter element more potently with ERβ than with ERα. Derivatives of GW-5638 with alterations at the carboxylic acid still showed increased ERβ potency compared to ERα, but the magnitude of the activation with ERα was much higher than with ERβ. Conclusions: Despite similar binding affinities to isolated ERα and ERβ, GW-5638 and GW-7604 show markedly lower EC₅₀ values with ERβ at an AP-1-driven promoter as compared to ERα. This suggests that the two compounds produce a more active ER/AP-1 conformation of the ER/AP-1 transcription factor complex when bound to ERβ than when bound to ERα.