Models of estrogen action. In the “classical” pathway of estrogen action (i), estrogen or other selective estrogen receptor modulators (SERMs) bind to the estrogen receptor (ER), a ligand-activated transcription factor that regulates transcription of target genes in the nucleus by binding to estrogen response element (ERE) regulatory sequences in target genes and recruiting coregulatory proteins (CoRegs) such as coactivators. Rapid or “nongenomic” effects of estrogen may also occur through the ER located in or adjacent to the plasma membrane (ii), which may require the presence of “adaptor” proteins, which target the ER to the membrane. Activation of the membrane ER leads to a rapid change in cellular signaling molecules and stimulation of kinase activity, which in turn may affect transcription. Lastly, other non-ER membrane-associated estrogen-binding proteins (EBPs) may also trigger an intracellular response (iii).