Molecular perspectives on selective estrogen receptor modulators (SERMs): progress in understanding their tissue-specific agonist and antagonist actions

Synthetic estrogen receptor ligands such as tamoxifen and raloxifene produce biologic responses which can be either estrogenic or anti-estrogenic, depending upon the tissue in which their action is examined. To reflect the fact that they are not 'pure' antagonists, such ligands have been more accurately termed selective estrogen receptor modulators (SERMs). Recent progress in our understanding of the molecular biology of estrogen receptor (ER) action has provided a great deal of evidence which promises to increase our understanding of the mechanism through which SERMs elicit their tissue-specific effects. The identification of numerous coactivators and corepressors which modulate receptor function and the realization of two subtypes of ER attest to the potential complexity through which SERMs produce diverse tissue-specific responses. Evidence from co-crystal structures of ER ligand-binding domains complexed with SERMs provides additional information as to how this class of ligands can elicit diverse biologic responses. SERMs also influence the stability of the ER protein, and recent information on the determinants of receptor stability and the role of proteasome-mediated protein degradation in ER-driven transcription also promises to give a fuller understanding of SERM biology. These aspects of the molecular biology of estrogen receptor action may help clarify the mechanism(s) of SERM biologic action and will be addressed in further detail in this review.