Putative functional characteristics of human estrogen receptor-beta isoforms

Abstract

Estrogen receptors (ERα and ERβ) are clearly multifaceted in terms of structure and function. Several relatively abundant ERβ isoforms have been identified, which can be differentially expressed in various tissues. In order to provide insight into the possible role of the ERβ family in breast tissue a study of the putative functions of the human (h) ERβ1, hERβ2 and hERβ5 isoforms was undertaken. Only hERβ1 was found to bind ligand, which induced conformational changes as determined by protease digestion assays. All ERβ isoforms could bind to and bend DNA although the relative efficiency with which they bound DNA differed with hERα>hERβ1>hERβ2>>hERβ5. All ERβ isoforms inhibited ERα transcriptional activity on an estrogen-response element (ERE)-reporter gene. The relative activities were hERβ1>hERβ2 >hERβ5; however, only hERβ1 had transcriptional activity of its own. Both LY117018-hERα and LY117018-hERβ1 complexes alone could activate transcription on a TGF-β3-CAT gene. Although hERβ2 and hERβ5 had no activity alone, they inhibited ERα but not hERβ1 transcriptional activity of transforming growth factor (TGF)-β3-CAT. In marked contrast to activity on an ERE-CAT reporter gene, hERβ1 did not modulate ERα transcriptional activity on a TGF-β3-CAT reporter gene. These data support promoter-specific differential activities of hERβ isoforms with respect to models of ERα regulated gene expression, and suggest that they may have a role in differentially modulating estrogen action.