Estrogen receptor (ER)-[beta] isoforms: a key to understanding ER-[beta] 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-[beta]1 tends to form heterodimers with other isoforms under the stimulation of estrogens but not phytoestrogens. Collectively, these data support the premise that (i) ER-[beta]1 is the obligatory partner of an ER-[beta] dimer, whereas the other isoforms function as variable dimer partners with enhancer activity, and (ii) a single functional helix 12 in a dimer is sufficient for gene transactivation. Thus, ER-[beta] 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-[beta] signaling and design of ER-[beta]-based therapies. estrogen responsive element | heterodimerization | molecular modeling | steroid receptor coactivator | type | nuclear receptor