Molecular mechanisms of selective estrogen receptor modulator (SERM) action

In females, estrogens play a key role in reproduction and have beneficial e ffects on the skeletal, cardiovascular, and central nervous systems. Most e strogenic responses are mediated by estrogen receptors (ERs), either ER alp ha or ER beta, which are members of the nuclear receptor superfamily of lig and-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues act like estrogens, but block estrogen action in others. Thus, SERMs may exhibit an agonistic or antagoni stic biocharacter depending on the context in which their activity is exami ned. For example, the SERMs tamoxifen and raloxifene both exhibit ER antago nist activity in breast and agonist activity in bone, but only tamoxifen ma nifests agonist activity in the uterus. Numerous studies have examined the molecular basis for SERM selectivity. Collectively they indicate that diffe rent ER ligands induce distinct structural changes in the receptor that inf luence its ability to interact with other proteins (e.g., coactivators or c orepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and of its target gene promoter affect SERM biocharacter. Taken togethe r, SERM selectivity reflects the diversity of ER forms and coregulators, ce ll type differences in their expression, and the diversity of ER target gen es. This model provides a basis for understanding the molecular mechanisms of SERM action, and should help identify new SERMs with enhanced tissue or target gene selectivity.