Estrogen receptor action through target genes with classical and alternative response elements

The estrogen receptors alpha and beta (ERα and ERβ) mediate the changes in gene expression from physiological and environmental estrogens. Early studies identified classical estrogen response elements (EREs) in the promoter region of target genes whose expression is regulated by estrogen and to which the ERs bind via their DNA-binding domain (DBD). EREs in the pituitary prolactin promoter, for example, mediate an activation by both ERα and ERβ albeit with different affinities for different ligands. Full activation in most cell types requires the integrity of the activation function 2 (AF-2) in the receptors ligand binding domain (LBD), which is engaged by estrogens and disengaged by tamoxifen, raloxifene, and other antiestrogens. However, in some cells and ERE contexts, the AF-1 in the ERα amino terminal domain (NTD) is sufficient. We now know that ERs also regulate expression of target genes that do not have EREs, but instead have various kinds of alternative response elements that bind heterologous transcription factors whose activity is regulated by interactions with ERs. Thus, ERα activates genes, including collagenase and cyclin D1, an important mediator of cellular proliferation, by AP-1 and CRE sites, which bind Jun/Fos or Jun/ATF-2 transcription factors. ERα also activates gene expression through GC-rich elements that bind the SP1 transcription factor. Finally, we also know that ERs mediate inhibition of the expression of many genes. In one well-studied instance, ERs counterexpression of genes involved in the inflammatory response by inhibiting the action at tumor necrosis factor response elements (TNF-REs) that bind the NFkappaB transcription factor. ERβ is especially efficient at this inhibition. ERα activation of AP-1/CRE target genes is of special interest because of the putative role of these target genes in mediating proliferation. The AF-1 and AF-2 functions of ERα are both needed for this activation in most cell types. However, in uterine cells, the AF-1 function is sufficient. Thus, the antiestrogen tamoxifen, which allows AF-1, mimics estrogen and drives activation of AP-1/CRE target genes and proliferation of uterine cells. This estrogen-like action, which can increase the risk of uterine cancer, complicates the use of tamoxifen to prevent breast cancer. Surprisingly, ERβ inhibits AP-1/CRE target genes in the presence of estrogen. When both receptors are present, ERβ efficiently opposes activation by ERα. Moreover, ERβ activates the AP-1/CRE target genes in the presence of antiestrogens especially so-called "complete" antiestrogens raloxifene, and ICI 182, 780. We here review the evidence for different kinds of promoter elements that mediate ER action, for the differential ligand preferences of ERα and ERβ at these different elements, and the potential mechanisms by which they are mediated. One attractive strategy for the investigation and comparison of potential environmental estrogens is to assay their activity in cell culture systems using reporter genes with simplified promoter elements. Thus, the findings of complexity in ERα and ERβ activation at different types of response elements needs to be taken into account in the development and interpretation of assays using simplified promoter elements systems.