Selective estrogen receptor modulators for BPH: new factors on the ground

Estrogen receptors (ERs) act by regulating transcriptional processes. The classical mechanism of ER action involves estrogen binding to receptors in the nucleus, after which the receptors dimerize and bind to specific response elements known as estrogen response elements (EREs) located in the promoters of target genes. However, ERs can also regulate gene expression without directly binding to DNA. This occurs through protein-protein interactions with other DNA-binding transcription factors in the nucleus. In addition, membrane-associated ERs mediate nongenomic actions of estrogens, which can lead both to altered functions of proteins in the cytoplasm and to regulation of gene expression. The latter two mechanisms of ER action enable a broader range of genes to be regulated than the range that can be regulated by the classical mechanism of ER action alone. This review surveys our knowledge about the molecular mechanism by which ERs regulate the expression of genes that do not contain EREs, and it gives examples of the ways in which the genomic and nongenomic actions of ERs on target genes converge. Genomic and nongenomic actions of ERs that do not depend on EREs influence the physiology of many target tissues, and thus, increasing our understanding of the molecular mechanisms behind these actions is highly relevant for the development of novel drugs that target specific receptor actions.

The biological actions of estrogens are mediated by estrogen binding to one of two specific estrogen receptors (ERs) ERalpha and ERbeta, which belong to the nuclear receptor superfamily, a family of ligand-regulated transcription factors. ERalpha and ERbeta are products of different genes and exhibit tissue- and cell-type specific expression. The characterization of mice lacking ERalpha, or ERbeta, or both has revealed that both receptor subtypes have overlapping but also unique roles in estrogen-dependent action in vivo. Additionally, ERalpha and ERbeta have different transcriptional activities in certain ligand, cell-type, and promoter contexts. Both receptors, however, are coexpressed in a number of tissues and form functional heterodimers. The biological roles of ERalpha /beta heterodimers in the presence of each respective homodimer are unknown. When coexpressed, ERbeta exhibits an inhibitory action on ERalpha -mediated gene expression and in many instances opposes the actions of ERalpha. A number of ERalpha and ERbeta isoforms have also been described, many of which alter estrogen-mediated gene expression. Uncovering the molecular mechanisms regulating the expression of both ERs, and how ERalpha and ERbeta directly or indirectly affect each other's function are paramount to understanding the cellular and biological events of estrogen-mediated gene regulation in normal and diseased tissues.