Complexity of SERM signal transduction

The decision network for estrogen or SERM action binding to nuclear estrogen receptor (ER) a or b receptor or membrane ER (decision 1). Receptor-specific or mixed specificity ligands bind to the ligand binding domain (E region) of the ERs to cause a ligand-specific perturbation in the receptor complex that creates opportunities for the complex to bind either coactivators or corepressors on the external surface (decision 2). The interactive proteins shunt the ER complex into transcriptionally active or inactive states. Although the expanding family of coregulators are being defined, this does not exclude the possibility that other interactive proteins could alter gene transcription through phosphorylation activation. This could be initiated rapidly either by membrane ER or constitutively through cell surface growth factor receptors. The next decision point (3) is where the complex or coregulators are ubiquitinated and destroyed by the proteasome or accumulate to become promiscuous estrogen-like complexes. Again, phosphorylation may play an important role in the activity of the ER complex. The decision (4) to interact with the machinery involved with gene transcription can shunt the signaling pathway from positive or negative regulation based upon the ER concerned, the ligand, or whether there is a direct interaction with an estrogen response element (ERE) or a tethered interaction to proteins at AP-1 or SP-1 sites. Overall, the decision network creates a complex regulatory system at target tissues or in cancer where a growth advantage can be exploited in response to antiestrogen therapies.