Estrogen receptor (ER)-β isoforms:: A key to understanding ER-β signaling

Estrogen receptor beta (ER-beta) regulates diverse physiological functions in the human body. Current studies are confined to ER-beta 1, and the functional roles of isoforms 2, 4, and 5 remain unclear. Full-length ER-beta 4 and -beta 5 isoforms were obtained from a prostate cell line, and they exhibit differential expression in a wide variety of human tissues/cell lines. Through molecular modeling, we established that only ER-beta 1 has a full-length helix 11 and a helix 12 that assumes an agonist-directed position. In ER-beta 2, the shortened C terminus results in a disoriented helix 12 and marked shrinkage in the coactivator binding cleft. ER-beta 4 and -beta 5 completely lack helix 12. We further demonstrated that ER-beta 1 is the only fully functional isoform, whereas ER-beta 2, -beta 4, and -beta 5 do not form homodimers and have no innate activities of their own. However, the isoforms can heterodimerize with ER-beta 1 and enhance its transactivation in a ligand-dependent manner. ER-PI tends to form heterodimers with other isoforms under the stimulation of estrogens but not phytoestrogens. Collectively, these data support the premise that (1) ER-beta 1 is the obligatory partner of an ER-13 dimer, whereas the other isoforms function as variable dimer partners with enhancer activity, and (h) a single functional helix 12 in a dimer is sufficient for gene transactivation. Thus, ER-P behaves like a noncanonical type-I receptor, and its action may depend on differential amounts of ER-beta 1 homo- and heterodimers formed upon stimulation by a specific ligand. Our findings have provided previously unrecognized directions for studying ER-13 signaling and design of ER-beta-based therapies.