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

Department of Environmental Health, Division of Environmental Genetics and Molecular Toxicology, College of Medicine, University of Cincinnati, OH 45267, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2006; 103(35):13162-7. DOI: 10.1073/pnas.0605676103
Source: PubMed


Estrogen receptor beta (ER-beta) regulates diverse physiological functions in the human body. Current studies are confined to ER-beta1, and the functional roles of isoforms 2, 4, and 5 remain unclear. Full-length ER-beta4 and -beta5 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-beta1 has a full-length helix 11 and a helix 12 that assumes an agonist-directed position. In ER-beta2, the shortened C terminus results in a disoriented helix 12 and marked shrinkage in the coactivator binding cleft. ER-beta4 and -beta5 completely lack helix 12. We further demonstrated that ER-beta1 is the only fully functional isoform, whereas ER-beta2, -beta4, and -beta5 do not form homodimers and have no innate activities of their own. However, the isoforms can heterodimerize with ER-beta1 and enhance its transactivation in a ligand-dependent manner. ER-beta1 tends to form heterodimers with other isoforms under the stimulation of estrogens but not phytoestrogens. Collectively, these data support the premise that (i) ER-beta1 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-beta1 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.

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    • "In order to confirm the specificity of the ERβ antibodies used in the study, we immunostained sections of human healthy liver, showing that ERβ1 and ERβ2 isoforms are not expressed, while specific nuclear ERβ5 immunoreactivity is detected (magnification 20x and 40x). This pattern of ERβ isoforms immunoreactivity is consistent with previous descriptions [18]. "
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    ABSTRACT: Background The male-to-female sex ratio for medulloblastoma (MB) is approximately 1.5∶1, female gender being also a favorable prognostic factor. This study aimed at evaluating the impact of gender on MB tumorigenesis. Methods In vitro activity of 17β-estradiol (E2), DPN [2,3-bis(4-hydroxyphenyl)-propionitrile, a selective estrogen receptor β (ERβ)-agonist], PPT [4,4′,4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol, a selective ERα-agonist] or DHT (5 alpha-dihydrotestosterone) was evaluated in three human MB cell lines. D283 Med cells were transplanted into athymic mice. Results A significant expression of ERβ, with little or no ERα, and low AR (androgen receptor) was found in MB cell lines. The compounds tested did not affect cell proliferation. In vivo, we observed a significantly lower growth of D283 Med in nude female mice compared to males. At microscopic examination, tumors from females showed a shift towards differentiation, as evaluated by lower nestin, and higher NSE (neuron-specific enolase) and GFAP (glial fibrillary acidic protein) expression compared to males. Tumors from females also showed lower Ki67 and p53 expression. The wild-type ERβ protein (ERβ1) was lost in male tumors, while it was a permanent feature in females, and a strong negative correlation was found between Ki67 and ERβ1 expression. Conversely, tumor levels of ERβ2 and ERβ5 did not significantly differ between genders. Increased levels of cyclin-dependent kinase inhibitor p21 were observed in females, suggesting that estrogen may decrease tumor growth through blocking cell cycle progression. An inhibition of the insulin-like growth factor I (IGF-I) signaling was also evident in females. Conclusion We provides mechanistic evidence supporting the idea that ERβ1 signaling may have pro-differentiation and tumor suppressive function in medulloblastomas.
    PLoS ONE 07/2014; 9(7):e101623. DOI:10.1371/journal.pone.0101623 · 3.23 Impact Factor
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    • "One possibility to explain the different behavior of 8beta-VE2 might be the propensity of the various ERbeta agonists to promote ERbeta homo- or heterodimerization. In line with this hypothesis, also phytoestrogens appear to favor only ERbeta1 homodimerization [17]. "
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    ABSTRACT: Prostate cancer (PC) progression from androgen-dependent (AD) to castration-resistant (CR) disease is a process caused by modifications of different signal transduction pathways within tumor microenvironment. Reducing cell proliferation, estrogen receptor beta (ERbeta) is emerging as a potential target in PC chemoprevention. Among the known selective ERbeta ligands, 3beta-Adiol, the endogenous ligand in the prostate, has been proved to counteract PC progression. This study compares the effects of chronic exposure (1-12 weeks) to different ERbeta selective ligands (DPN, 8beta-VE2, 3beta-Adiol) on proliferation of human androgen-responsive CWR22Rv1 cells, representing an intermediate phenotype between the AD- and CR-PC. 3beta-Adiol (10 nM) is the sole ligand decreasing cell proliferation and increasing p21 levels. In vitro transcriptional activity assays were performed to elucidate different behavior between 3beta-Adiol and the other ligands; in these experiments the endogenous and the main ERbeta subtype activation were considered. It is concluded that ERbeta activation has positive effects also in androgen-responsive PC. The underlying mechanisms are still to be clarified and may include the interplay among different ERbeta subtypes and the specific PC microenvironment. ERbeta agonists might be useful in counteracting PC progression, although the final outcome may depend upon the molecular pattern specific to each PC lesion.
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    • "We also outline the studies that have described the possible ER-and PR-mediated signaling pathways that contribute to the disease. ER subtype expression in human endometrio- sis There are two structurally related ER subtypes, ERα and ERβ, that appear to have overlapping, but different, tissue expression and localization profiles and ligand specificities [15] [16]. In general , binding of the ligand to the ER results in the dissociation of heat shock proteins from the ER that allows the receptors to form dimers (ERα/ERα, ERβ/ERβ, or ERα/ERβ) [17]. "
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