{"paper_id":"3222b37c-86d4-4c7d-92d1-6941074c9290","body_text":"DOI: 10.1530/JME-16-0080\nhttp://jme.endocrinolovgy-journals.org © 2016 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\n57: 2\nJournal of Molecular Endocrinology\nF23–F27r c m  simmen  and a  s kelley Estrogen receptor-β  multitasks\nFocused Review\n10.1530/JME-16-0080\nAbstract\nEnhanced inflammation and reduced apoptosis sustain the growth of endometriotic \nlesions. Alterations in the expression of estrogen receptor-alpha (ERα ) and estrogen \nreceptor-beta (ERβ) accompany the conversion of resident endometrial cells within the \nnormal uterine environment to ectopic lesions located in extrauterine sites. Recent \nstudies highlighted in this focused review linked ERβ  to dysregulation of apoptotic \nand inflammatory networks involving novel interacting partners in endometriosis. The \nelucidation of these nongenomic actions of ERβ  using human cells and mouse models is \nan important step in understanding key regulatory pathways that are disrupted leading \nto disease establishment and progression.\nEstrogens are key mediators of endometrial homeostasis; \nhence, any dysregulation in their synthesis, metabolism, \nand/or activities irrefutably leads to a broad range of \nendometrial pathologies. Two major estrogen receptor \nproteins, estrogen receptor-alpha (ERα ) and estrogen \nreceptor-beta (ERβ ) which are encoded by distinct \ngenes (White et  al. 1987, Kuiper et  al. 1996), mediate \nthe actions of estrogens in target cells. The significant \nhomologies in DNA (94%) and ligand-binding domains \n(59%) between these ERs enable both proteins to bind \nestrogens with equal affinity and to transcriptionally \nregulate common subsets of ER-responsive genes. \nERα and ERβ  display distinct spatial, temporal, and \nphysiological expression. Genetic deletions support \nmost roles for ERα in the uterus and for ERβ to prevail in \nthe ovary (Hamilton et al. 2014). Although ligand-bound \nERα is a requisite for mitogenesis of uterine cells, ERβ  is \nconsidered to inhibit ERα-dependent cell proliferation in \npart, through its ability to form ERα /ERβ heterodimers \nwith different ligand specificity, interacting partners, \nand transcriptional targets than ERα  homodimers  \n(Pace et al. 1997).\nEndometriosis is an estrogen-dependent gynecological \ndisorder, defined as the growth of endometrial stroma and \nglands in extrauterine sites such as in the peritoneum and \nthe ovary (Burney & Giudice 2012). The disease affects 1 \nin 10 reproductive age women and can lead to debilitating \npelvic pain, dysmenorrhea, and reduced fertility. Although \nbenign, endometriosis is a chronic condition that requires \nlong-term treatment throughout a woman’s reproductive \nyears. The goals of treatment for endometriosis include \nhormonal suppression of active endometriosis or surgical \nexcision/ablation of visible lesions (Vercellini et al. 2014). \nHowever, medical therapies are not without side effects \nand surgical removal of the ovaries and uterus, although \nconsidered a definitive management for the condition, is \nnot without associated morbidity.\nIn recent years, ERβ  has emerged as an important \nplayer in the pathogenesis of endometriosis. Human \nendometriotic lesions, whether of ovarian or peritoneal \nCorrespondence  \nshould be addressed  \nto R C M Simmen  \nEmail  \nsimmenrosalia@uams.edu\nReversal of fortune: estrogen \nreceptor-β in endometriosis\nRosalia C M Simmen1 and Angela S Kelley2\n1Department of Physiology and Biophysics, University of Arkansas for Medical Sciences,  \nLittle Rock, Arkansas, USA\n2Department of Obstetrics and Gynecology, University of Michigan Health System,  \nAnn Arbor, Michigan, USA\n57:2\nKey Words\n f endometriosis\n f estrogen receptor-beta\n f inflammation\n f non-genomic\n f apoptosome\nJournal of Molecular \nEndocrinology  \n(2016) 57, F23–F27\nDownloaded from Bioscientifica.com at 06/27/2026 07:07:53PM\nvia free access\n\n\nJournal of Molecular Endocrinology\nDOI: 10.1530/JME-16-0080\nhttp://jme.endocrinology-journals.org © 2016 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nF24Focused Review\n 57 2: F24Focused Review 57 2:\n \nJournal of Molecular Endocrinology\nDOI: 10.1530/JME-16-0080\nhttp://jme.endocrinology-journals.org © 2016 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nF24\nr c m  simmen  and a  s kelley Estrogen receptor-β  multitasks57 2: F2457 2:\nFocused Review\nlocations, display higher ERβ  expression compared with \nnormal human endometrial cells; this was not shown for \nERα (Bulun et al. 2012). The reversal in the ERβ -to-ERα \nratio in lesions (>>1), relative to normal endometrial cells \n(<<1), has been similarly demonstrated in many animal \nmodels of endometriosis (Fazleabas et al. 2003, Greaves \net  al. 2014, Heard et  al. 2014). It raises the intriguing \nquestion of how the conventionally antiproliferative \nERβ in the endometrium, in the context of endogenous \nestrogens, dismantles its customary role and orchestrates \na pro-proliferative/antiapoptotic/proinflammatory \nresponse to drive disease pathogenesis. In a recent issue \nof Cell ( Han et al. 2015), an elegant study by O’Malley \nand coworkers unequivocally demonstrated that ERβ \nis required for the progression of endometriosis in \nmice and defined the apoptosome and inflammasome \nas endogenous targets of nongenomic ERβ  action. \nKatzenellenbogen and colleagues in a related study \npublished in Science Translational Medicine ( Zhao et  al. \n2015) described two ER antagonists, one specific for ERα \n(chloroindazole (CLI)) and the other specific for ERβ \n(oxabicycloheptane sulfonate (OBHS)), that individually \nfunction to inhibit the estrogen-inflammatory axis \nto suppress endometriosis in mice. These two studies \ncollectively define a novel role for ERβ  in the upper \nechelon of the inflammatory regulatory hierarchy. \nImportantly, as inflammation is well considered as \none of the major contributors to the development \nand progression of endometriosis, the study findings \noffer promise for novel therapeutic strategies that may \nbe relevant to endometriosis and other reproductive \nand nonreproductive diseases associated with chronic \ninflammation.\nTo uncover the underlying mechanism(s) by which \nERβ promotes endometriosis, O’Malley and his group used \novariectomized+E\n2-pelleted immunocompetent mouse \nmodels in which endometriosis was surgically induced \nthrough autotransplantation of ERβ-overexpressing \n(ERβ-OE) (gain-of-ERβ-function) and ERβ-null (loss-of-\nERβ-function) endometrial tissues in the peritoneal cavity. \nEctopic lesions generated from ERβ-OE endometrium had \nlarger volumes, whereas those from ERβ-null endometrium \nhad smaller volumes, than did wild-type (WT; control) \nectopic lesions. Consistent with these observations, the use \nof the ERβ-selective antagonist PHTPP (a pyrazolo[1,5-α]\npyrimidine-based ligand) suppressed ectopic lesion \ngrowth relative to vehicle alone. The inhibitory effect of \nPHTPP on lesion growth was accompanied by the loss of \nrecruitment of CD163-positive monocyte/macrophage \ncells that normally infiltrate lesions. Conversely, the  \nERβ-specific agonist ERB-041 enhanced the growth of \nmouse ectopic lesions compared with vehicle alone. \nBecause these noted changes in lesion growth occurred \nin the absence of perturbations in ERα, enhanced ERβ \nexpression and activity appear sufficient to promote \nendometriosis progression. In an earlier study (Harris \net al. 2005), athymic nude mice surgically implanted with \nhuman endometriotic lesions showed lesion regression \nwhen administered ERB-041, a response clearly contrasting \nwith that obtained with the immunocompetent mouse \nmodel in the Cell study. Intriguingly, ectopic lesions \nformed in control and ERB-041-treated nude mice did not \nexpress ERβ, a major departure from lesions of women and \nthose generated in other animal models of endometriosis, \nin which ERβ is the predominant ER isoform. Although \nthe molecular basis underlying the differential responses \nof the two mouse models to ERB-401 remains unknown, \nthese results provide support for the complex interactions \nbetween the immune system and ER-mediated signaling \nin the development and progression of endometriosis. \nAdditionally, these results highlight innate limitations of \nthe animal models utilized for many endometriosis studies, \nincluding those described in the two highlighted papers \nin this review (e.g., the need to implant estrogen pellets, \nwhich most likely does not reflect/only approximates the \nsituation in humans) and underscore the continuing need \nfor the development of more relevant models to fully \nunderstand the human disease.\nHow might ERβ  alter lesion biology distinct from \nits role in nondiseased endometrial cells? The authors \nanalyzed by mass spectroscopy flag-tagged ERβ-containing \nprotein complexes that were immunoprecipitated \nfrom eutopic endometria of endometrial ERβ -OE mice. \nFurther confirmation by Western blotting revealed that \na majority of proteins interacting with ERβ  are involved \nin inflammation and apoptosis signaling. Apoptosis plays \nan important role in inflammation and in the resolution \nof inflammatory reactions, and the two are irrefutably \nlinked because cell death signaling initiated by tumor \nnecrosis factor-alpha (TNF-α ) activates inflammasomes \nto initiate IL-1β -driven inflammation (Vince & Silke \n2016). An attractive candidate identified in the study \nas an ERβ -interacting protein is apoptosis signal-\nregulating kinase-1 (ASK-1). ASK-1 is a component of \nTNF-α-induced apoptosis complex 1, whose formation is \nrequired for TNF-α -induced apoptosis. Serine/threonine \nkinase receptor-associated protein (STRAP) and 14-3-3 \nprotein were also identified to interact with ERβ  in the \nsame screen. Interestingly, STRAP and 14-3-3 proteins \nhave been previously demonstrated to bind ASK-1 in a \nDownloaded from Bioscientifica.com at 06/27/2026 07:07:53PM\nvia free access\n\n\nJournal of Molecular Endocrinology\nDOI: 10.1530/JME-16-0080\nhttp://jme.endocrinology-journals.org © 2016 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nF25 \n 57 2:\nJournal of Molecular Endocrinology\nDOI: 10.1530/JME-16-0080\nhttp://jme.endocrinology-journals.org © 2016 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nF25\nr c m  simmen  and a  s kelley Estrogen receptor-β  multitasks57 2:\nFocused Review\ntripartite complex (Jung et  al. 2010). The formation of \nthis complex interferes with the functional association \nbetween ASK-1 and the TNF receptor-associated factor 2 \nin response to TNF-α signaling, resulting in the inhibition \nof TNF-α-induced apoptosis. To validate this model, the \nauthors demonstrated (i) lower status of phosphorylated \nASK-1 (phospho-Thr845 ASK-1), without accompanying \nchanges in total ASK-1 protein levels, indicating loss \nof ASK-1 activation and hence, function in ERβ -OE \nectopic lesions compared with WT ectopic lesions; (ii) \nconversely, increased levels of phosphorylated ASK-1 \nin ERβ-null ectopic lesions compared with WT ectopic \nlesions; and (iii) lower mitochondrial cytochrome c levels \nin ERβ-OE ectopic lesions, consistent with the disruption \nof TNF-α -induced ASK-1 activation that normally leads \nto caspase 1 (Cas1) activation. The link between ERβ \nand Cas1 was further illuminated by demonstrating \nthat ERβ -OE ectopic lesions had lower Cas1 levels \nand lacked detectable interactions between Cas1 and \napoptotic peptidase-interacting factor; by contrast, the \nlatter interaction was easily detected in ERβ -null ectopic \nlesions. Taken together, these novel findings identify \nTNF-α-induced apoptosis as a key regulatory pathway \ndisrupted by cytoplasmic-based ERβ  to promote lesion \nsurvival. The cytoplasmic-localized ERβ  antiapoptotic \naction likely occurs in conjunction with nuclear-localized \nERβ transcriptional activation of gene targets such as \nthe serum and glucocorticoid-regulated kinase, which, \nby phosphorylating the proapoptotic FOXO3, inhibits \napoptosis (Monsivais et al. 2016). However, the relative \ncontribution of nuclear vs cytoplasmic actions of ERβ  to \nlesion survival is unknown.\nThe intriguing idea that ERβ multitasks outside of the \nnucleus was further demonstrated in other experiments \nfrom the same study. The authors identified caspase-1 and \nthe NLR family pyrin domain-containing 3 as additional \nERβ-interacting proteins. These findings are significant \nin the context of the inflammatory process, given the \nrequisite participation of caspase-1 and NLR in the \nprocessing of pro-IL-1β to the mature bioactive IL-1β, a \nkey regulator of adhesion and proliferation in endometrial \ncells (Kao et al. 2011). In this regard, ERβ-OE lesions had \nhigher IL-1β and cleaved caspase-1 levels than did control \nectopic lesions; conversely, ERβ-null lesions had lower \nlevels of both components. Given that primary human \nendometriotic stromal cells also showed elevated levels of \nIL-1β and increased antiapoptosis signaling when treated \nwith TNF-α, the results suggest that the key ERβ-mediated \nevents elucidated in these mouse models of endometriosis \nare relevant to the human disease.\nInterestingly, the authors found, using immortalized \nhuman endometrial epithelial cells expressing Myc-\ntagged human ERα genes, that TNF-α treatment of these \ncells did not elicit comparable antiapoptotic responses \nand an increase in IL-1β expression as noted for the \nsame human cells expressing ERβ. More intriguingly, \ncotransfection of ERα and ERβ in these cells resulted \nin ERα inhibition of ERβ-mediated IL-1β production, \nsuggesting that ERα may assume a negative regulatory role \nin ERβ-mediated promotion of inflammation. Whether \nthis effect of ERα reflects its competitive displacement \nof ERβ from its interacting proteins or its sequestering \nof ERβ through formation of ERα/ERβ heterodimers is \nunknown. This result, while baffling, sheds new light on \nthe contrasting activities of ERβ and ERα in endometriosis \nand must be reconciled with previous findings that \nERα is an equally active player in the pathology of \nthis disease in mice (Burns et al. 2012). In the study by \nKatzenellenbogen and colleagues (Zhao et  al. 2015), \nspecific ERα (CLI) and ERβ (OBHS) antagonists exhibited \nER-dependent anti-inflammatory activities in a mouse \nmodel of endometriosis and in human endometriotic \nstromal cells. In these models, CLI and OBBHS equally \ninhibited estrogen-dependent processes, including cell \nproliferation, cyst formation, vascularization, cytokine \nproduction, macrophage infiltration and lesion growth. \nA previous study has reported the presence of both ERα \nand ERβ in peritoneal fluid macrophages and shown that \nboth ERs display higher expression in peritoneal fluid \nmacrophages of women with endometriosis compared \nwith women without endometriosis (Montagna et  al. \n2008). Interestingly, this same study showed that only \nERα expression was positively correlated with increased \nproinflammatory cytokine levels in peritoneal fluids of \nwomen with endometriosis. ERβ levels, while higher in \nperitoneal fluid macrophages of women with endometriosis, \nwere correlated with the expression of proinflammatory \ncytokines, irrespective of disease status, suggesting a role \nfor macrophage ERβ in basal proinflammatory cytokine \nproduction and for macrophage ERα as a likely ‘driver’ \nof increased inflammation seen in endometriosis. As \nmouse ectopic lesions, similar to human lesions, display \nhigher levels of ERβ than ERα, one intriguing question \nraised by the Katzenellenbogen study pertains to the \nunexpected comparable levels of inhibition of estrogen-\ndependent responses with disruption of ERα signaling to \nthat mediated by the more highly expressed ERβ. Perhaps \nthe significant contribution of recruited macrophages \nexpressing higher ERα, and hence equally higher \nproduction of pro-inflammatory cytokines, may underlie \nDownloaded from Bioscientifica.com at 06/27/2026 07:07:53PM\nvia free access\n\n\nJournal of Molecular Endocrinology\nDOI: 10.1530/JME-16-0080\nhttp://jme.endocrinology-journals.org © 2016 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nF26 \n 57 2: F26 57 2:\nJournal of Molecular Endocrinology\nDOI: 10.1530/JME-16-0080\nhttp://jme.endocrinology-journals.org © 2016 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nF26\nr c m  simmen  and a  s kelley Estrogen receptor-β  multitasks57 2: F2657 2:\nFocused Review\nthe favorable response of lesions to ERα antagonists.  \nIt is also tempting to speculate that the cellular locations \nof the respective actions of ERα and ERβ may be at play, \ngiven that in the O’Malley’s study, ERβ disruption of \ninflammasome and apoptosome functions takes place \noutside of the nucleus, invoking nongenomic actions and \ninvolving novel interactions with proteins not previously \nidentified to interact with ERβ. If the latter is true, then a \nfollow-up question is whether ERα interacts (or not) with \nsome of the same proteins that were identified for ERβ. \nYet another question is whether ERβ preferentially acts \noutside of the nucleus in endometriotic lesions and if this \nmay underlie the reversal of its (generally good) fortune \nof being the better half to ERα in controlling mitogenesis. \nThe answer is not likely going to be straightforward given \nother nuclear actions attributed to ERβ in ectopic lesions, \none of which is its transcriptional regulation of ERα in \nendometriotic stromal cells (Trukhacheva et  al. 2009). \nTime (and more in-depth scrutiny) will tell.\nThe molecular details of complex mechanisms \nhave gained much ground from careful dissection of \ncontext-dependent cross talk among seemingly unrelated  \nmole cules. For an enigmatic condition such as \nendometriosis, the identification of novel partners \nelucidated here for ERβ begs the question of whether \nprogesterone receptors (whose expression and function are \nequally compromised in endometriosis) and other steroid \nreceptor coactivators or corepressors may similarly assume \nnew extranuclear (cytoplasmic) roles to sustain ectopic \ngrowth. A tip-off to this possibility comes from the recent \ndiscovery of a new 70 kDa (truncated) steroid receptor \ncoactivator 1 (SRC-1) isoform, which, similar to ERβ, was \nfound to have little expression in normal endometrium, \nbut displayed a significant expression in endometriotic \nlesions (Han et al. 2012). Moreover, the truncated SRC-1 \nprotein, similar to ERβ, was demonstrated to be essential \nin the initial stages of endometriosis establishment. In \nthe current Cell paper, SRC-1 isoform was shown to form \na complex with ERβ and caspase-8, inhibiting the latter \nfrom interacting with its usual partner Fas-associated via \ndeath domain protein to generate apoptosis complex II \nthat augments TNF-α-induced apoptosis. Whether the \ntruncated SRC-1 only partners with ERβ or exhibits a more \nexpansive repertoire of interacting proteins to promote \nendometriosis remains to be explored.\nThe present studies provide fundamental insights \ninto the adaptive functions of ERβ in inflammation \nand apoptosis (Fig. 1). Fine-tuning our awareness of the \nFigure 1\nProposed model for ERβ regulation of inflammation and apoptosis in endometriotic lesions. Normal endometrium and ectopic lesions display distinct \nlevels of ERα and ERβ. The direct interactions of ERβ with proteins associated with inflammation and apoptosis in ectopic lesions (Han et al. 2015) \nprovide novel, nongenomic mechanisms for ERβ-mediated pathogenesis of endometriosis. CLI and OBHS are, respectively, specific ERα and ERβ \nantagonists shown to inhibit ER-mediated promotion of inflammation underlying endometriosis progression (Zhao et al. 2015). ASK-1, STRAP, 14-3-3, \nNLR, Cas1, and IL-1β are defined in the text.\nDownloaded from Bioscientifica.com at 06/27/2026 07:07:53PM\nvia free access\n\n\nJournal of Molecular Endocrinology\nDOI: 10.1530/JME-16-0080\nhttp://jme.endocrinology-journals.org © 2016 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nF27 \n 57 2:\nReceived in final form 27 May 2016\nAccepted 7 June 2016\nAccepted Preprint published online 7 June 2016\nJournal of Molecular Endocrinology\nDOI: 10.1530/JME-16-0080\nhttp://jme.endocrinology-journals.org © 2016 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nF27\nr c m  simmen  and a  s kelley Estrogen receptor-β  multitasks57 2:\nFocused Review\ndifferent networks orchestrated by steroid hormone \nreceptors and their changing partners in normal \nand endometriotic cells may offer the much-needed \ntherapeutic opportunities to address the development \nand progression of endometriosis.\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be \nperceived as prejudicing the impartiality of this review.\nFunding\nThis work was supported in part by the National Institutes of Health \n(RO1CA136493, UL1TR000039) and the Arkansas Biosciences Institute \nIntramural Grant Program.\nReferences\nBulun SE, Monsavais D, Pavone ME, Dyson M, Xue Q, Attar E, \nTokunaga H & Su EJ 2012 Role of estrogen receptor-β in \nendometriosis. 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