Estrogen receptor transcription and transactivation: Basic aspects of estrogen action

Jensen and Jacobsen were the first to describe that the biological effects of estrogen are mediated by a receptor protein [1]. The cloning of the ER, today renamed ERα, was reported in 1986 [2,3]. For a long time, it was believed that only one ER existed; however, in 1995 a second ER, ERβ, was cloned from a rat prostate cDNA library by Gustafsson and colleagues [4**]. This finding has lead to a paradigm shift in our understanding of estrogen action, as will be evident from the different reviews in this issue of Breast Cancer Research.Since the discovery of ERβ in rat prostate, several groups have reported the cloning of ERβ from other species [5,6,7] or different sized ERβ isoforms, some with extended N-termini and others with truncations and/or insertions in the C-terminal ligand binding domain (LBD). The original ERβ clone encodes a protein of 485 amino acids, designated ERβ-485. ERβ-503 has an 18 amino acid residue in frame insertion into the LBD, and has a considerably lower affinity for E2 than ERβ-485. Both ERβ-503 and ERβ-485 bind to a consensus estrogen response element (ERE) and heterodimerize with each other and with ERβ [8,9]. The coactivator SRC-1 interacts with both ERα and ERβ-485 in an estrogen-dependent manner but not with ERβ-503 [9]. An additional ERβ isoform, ERβcx [10], is identical to ERβ-530 except that the last 61 C-terminal amino acids (exon 8) are replaced by 26 unique amino acid residues. The ERβcx isoform shows no ligand binding activity and has no capacity to activate transcription of an estrogen-sensitive reporter gene [10]. Furthermore, ERβcx shows preferential heterodimerization with ERα rather than with ERβ, inhibiting ERα DNA binding and having a dominant negative effect on ligand-dependent ERβ reporter gene transactivation [10].Various alternatively spliced forms of ERα have also been reported [11,12,13,14,15,16]. Whether all isoforms or differentially spliced versions of ERα and ERβ, respectively, are expressed as proteins or have