Action of selective estrogen receptor modulators (SERMs) through the classical mechanism of estrogen action

Abstract

The molecular mechanisms through which SERMs have an estrogen-agonistor antagonist effect, depending on the tissue in question, has been a topic ofintense investigation during the last decade (Yang et al. 1996b; Shang et al.2002; Meegan et al. 2003; Smith et al. 2004). Recent advances in the molecularbiology of ERs have revealed the enormously complex nature of this process.As mentioned in Chapter XXX, estrogens regulate the activation of genes bymeans of a series of molecular events triggered after they bind to the estrogenreceptor (ER), which is simply a transcription factor that can be activated bya ligand. The same course of events is set inmotion by selective estrogen receptormodulators (SERMs). In short, the high-affinity binding to the ER, and tothe ER alone, is a fundamental characteristic of SERMs. The absence of crossbindingwith other members of the nuclear receptor superfamily (androgen,progesterone, glucocorticoids, mineralocorticoids, retinoic acid, vitamin Dreceptors, etc.) is a critical stage in the target molecule selection process.The binding of the ligand to the ER leads to a conformational change in theligand-ER complex, causing disassociation of the stress proteins associated tothe inactive receptor (heat-shock proteins). The inactive receptors, which aremonomers in basal conditions, dimerize and get phosphorylated until they finallybind to a series of nuclear proteins called adaptor or coregulator proteins.This ligand-ER complex binds to one of the DNA response elements (EREs:estrogen response elements), generally located in the promoter region of estrogentarget genes, and trigger the mRNA transcription and synthesis process.Depending on the cell type, coregulator protein load, ratio of coactivator andcorepressor proteins, and different gene promoters, the ligand-ER dimer mayactivate or inhibit the gene transcription.It isof great interest that newfindings suggest that several effects of estrogenand SERMs also may be mediated by nonnuclear ER actions derived from fastactivation (in a matter of minutes) of the protein-kinase cascades and othersignaling processes associated to cell membrane ERs. These activation routes,described in detail in Chap. 1 by Escrich et al. are not mediated by transcription factors and nuclear ER activation. The functional effects associated withthese pathways include some of the cardiovascular effects of estrogens, such asnitric oxide (NO)-dependent vasodilatation, inhibition of endothelial damageresponse, and reduced ischemic damage to the myocardium in experimentalconditions (Ho et al. 2002; Salom et al. 2002). Raloxifene and its analogLY-117018 stimulate endothelial NO synthetase (eNOS) and lead to coronaryartery relaxation and improved vasodilatation in hypertensive rats (Simonciniet al. 2002a; Wassman et al. 2002). The eNOS activation by means of protein-kinase activation (MAPKs and PI3K-Akt) has also been reported with EM-800(Simoncini et al. 2002b). These nongenomic pathways of estrogen action havealso been reported in neuronal cells (Qiu et al. 2003) and bone cells (Kousteniet al. 2003), but their contribution in the action of specific SERM compounds,and the role of different signaling pathways in tissue-specific actions, is undefinedat this time.In addition to these rapid nongenomic events, the pharmacodynamic profileof different SERMs may depend on the subtle mesh of the combined action ofcomplex mechanisms that govern the transcriptionmediated by ERs. Basically,this can occur at four levels: (1) tissue amount and distribution of the differentERsubtypes; (2) impact on binding capacity to promoters provoking the different3D conformations of the SERM-ligand complex, which ultimately dictatespecific coregulator interactions; (3) different content of nuclear coregulatorproteins (coactivators and corepressors) in various cells; and (4) presence ofdifferent types of estrogen response elements (EREs) in the gene promoters,including the ability of ERs to affect gene expression without directly bindingto target DNAs in a process known as transrepression. © Springer-Verlag Berlin Heidelberg 2006.