{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:52:04Z","timestamp":1781157124161,"version":"3.54.1"},"reference-count":44,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Endometriosis is an estrogen-dependent, inflammation-driven gynecologic disorder in which endometrial tissue creates inflammatory lesions at extrauterine sites, leading to pelvic pain and impaired fertility. Although dysregulated estrogen receptor (ER) signaling has been implicated, understanding of this disease is incomplete and current therapies are of limited benefit. Using an immunocompetent syngeneic murine model, we used combinations of donor uterine tissue and\/or recipient host mice with partial genetic deletion of the ER coregulator, repressor of ER activity (REA) (also known as prohibitin 2), to investigate roles of REA in the contributions of donor uterine tissue and host cell influences on endometriosis establishment and progression. Ectopic lesions derived from donor tissue with half the wild-type gene dosage of REA (REA+\/\u2212) grown in REA+\/\u2212 hosts displayed enhanced proliferation, vascularization, and markedly increased neuron innervation and inflammatory responses, including elevated cytokine production, nuclear factor kappa B activation, cyclooxygenase-2 expression, and immune cell infiltration. Although lesion progression was greatest when REA was reduced in both donor tissue and host animals, other donor\/host combinations indicated that distinct stimulatory inputs were derived from ectopic tissue (proliferative signals) and host cells (inflammatory signals). Importantly, depletion of REA in primary human endometriotic stromal cells led to elevated proliferation and expression of cell cycle regulators. Notably, REA was significantly lower in human endometriotic tissue versus normal human endometrium. Thus, REA modulates cross talk among multiple cell types in the uterine tissue and host background, serving as a brake on the estradiol-ER axis and restraining multiple aspects that contribute to the pathologic progression of endometriosis.<\/jats:p>","DOI":"10.1210\/en.2015-1324","type":"journal-article","created":{"date-parts":[[2015,12,14]],"date-time":"2015-12-14T18:03:12Z","timestamp":1450116192000},"page":"900-912","source":"Crossref","is-referenced-by-count":16,"title":["Multiple Beneficial Roles of Repressor of Estrogen Receptor Activity (REA) in Suppressing the Progression of Endometriosis"],"prefix":"10.1210","volume":"157","author":[{"given":"Yuechao","family":"Zhao","sequence":"first","affiliation":[{"name":"Departments of Molecular and Integrative Physiology (Y.Z., Y.C., M.K.B., B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiru","family":"Chen","sequence":"first","affiliation":[{"name":"Departments of Molecular and Integrative Physiology (Y.Z., Y.C., M.K.B., B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Kuang","sequence":"first","affiliation":[{"name":"Department of Gynecology and Obstetrics (Y.K.), The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milan K.","family":"Bagchi","sequence":"first","affiliation":[{"name":"Departments of Molecular and Integrative Physiology (Y.Z., Y.C., M.K.B., B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert N.","family":"Taylor","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Katzenellenbogen","sequence":"first","affiliation":[{"name":"Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benita S.","family":"Katzenellenbogen","sequence":"first","affiliation":[{"name":"Departments of Molecular and Integrative Physiology (Y.Z., Y.C., M.K.B., B.S.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2015,12,14]]},"reference":[{"key":"2020071612015746000_B1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1146\/annurev-physiol-012110-142158","article-title":"Endometriosis: the role of neuroangiogenesis","volume":"73","author":"Asante","year":"2011","journal-title":"Annu Rev Physiol"},{"key":"2020071612015746000_B2","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.mce.2008.12.012","article-title":"Steroidogenic factor-1 and endometriosis","volume":"300","author":"Bulun","year":"2009","journal-title":"Mol Cell Endocrinol"},{"key":"2020071612015746000_B3","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/S0140-6736(04)17403-5","article-title":"Endometriosis","volume":"364","author":"Giudice","year":"2004","journal-title":"Lancet"},{"key":"2020071612015746000_B4","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1177\/1933719111410713","article-title":"Novel therapies targeting endometriosis","volume":"18","author":"Taylor","year":"2011","journal-title":"Reprod Sci"},{"key":"2020071612015746000_B5","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.4049\/jimmunol.0902383","article-title":"17\u03b2-estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor \u03b1 signaling in macrophages in vivo","volume":"185","author":"Calippe","year":"2010","journal-title":"J Immunol"},{"key":"2020071612015746000_B6","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.4049\/jimmunol.1101578","article-title":"Estrogen receptor \u03b1 signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis","volume":"187","author":"L\u00e9lu","year":"2011","journal-title":"J Immunol"},{"key":"2020071612015746000_B7","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.cmet.2014.05.013","article-title":"The cholesterol metabolite 27-hydroxycholesterol promotes atherosclerosis via proinflammatory processes mediated by estrogen receptor \u03b1","volume":"20","author":"Umetani","year":"2014","journal-title":"Cell Metab"},{"key":"2020071612015746000_B8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0889-8545(02)00050-5","article-title":"The epidemiology of endometriosis","volume":"30","author":"Missmer","year":"2003","journal-title":"Obstet Gynecol Clin North Am"},{"key":"2020071612015746000_B9","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1210\/jcem-54-5-1081","article-title":"\u201cMedical oophorectomy\u201d using a long-acting GNRH agonist\u2013a possible new approach to the treatment of endometriosis","volume":"54","author":"Meldrum","year":"1982","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612015746000_B10","first-page":"174","article-title":"Aromatase expression in endometriosis","volume":"81","author":"Noble","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612015746000_B11","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1093\/molehr\/5.7.651","article-title":"Oestrogen receptor (ER)-\u03b1 and ER-\u03b2 isoforms in normal endometrial and endometriosis-derived stromal cells","volume":"5","author":"Brandenberger","year":"1999","journal-title":"Mol Hum Reprod"},{"key":"2020071612015746000_B12","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1095\/biolreprod.107.061804","article-title":"Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis","volume":"77","author":"Xue","year":"2007","journal-title":"Biol Reprod"},{"key":"2020071612015746000_B13","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1093\/humupd\/dml026","article-title":"Animal models in endometriosis research","volume":"12","author":"Gr\u00fcmmer","year":"2006","journal-title":"Hum Reprod Update"},{"key":"2020071612015746000_B14","doi-asserted-by":"crossref","first-page":"3960","DOI":"10.1210\/en.2012-1294","article-title":"Role of estrogen receptor signaling required for endometriosis-like lesion establishment in a mouse model","volume":"153","author":"Burns","year":"2012","journal-title":"Endocrinology"},{"key":"2020071612015746000_B15","doi-asserted-by":"crossref","first-page":"3226","DOI":"10.1210\/en.2010-1010","article-title":"Treatment with bazedoxifene, a selective estrogen receptor modulator, causes regression of endometriosis in a mouse model","volume":"152","author":"Kulak","year":"2011","journal-title":"Endocrinology"},{"key":"2020071612015746000_B16","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1093\/humrep\/deh711","article-title":"A selective estrogen receptor-\u03b2 agonist causes lesion regression in an experimentally induced model of endometriosis","volume":"20","author":"Harris","year":"2005","journal-title":"Hum Reprod"},{"key":"2020071612015746000_B17","doi-asserted-by":"crossref","first-page":"271ra279","DOI":"10.1126\/scitranslmed.3010626","article-title":"Dual suppression of estrogenic and inflammatory activities for targeting of endometriosis","volume":"7","author":"Zhao","year":"2015","journal-title":"Sci Transl Med"},{"key":"2020071612015746000_B18","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1111\/j.1582-4934.2006.tb00404.x","article-title":"The Prohibitins: emerging roles in diverse functions","volume":"10","author":"Mishra","year":"2006","journal-title":"J Cell Mol Med"},{"key":"2020071612015746000_B19","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.chembiol.2013.02.006","article-title":"Prohibitin ligands in cell death and survival: mode of action and therapeutic potential","volume":"20","author":"Thuaud","year":"2013","journal-title":"Chem Biol"},{"key":"2020071612015746000_B20","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1128\/MCB.25.5.1989-1999.2005","article-title":"Genetic deletion of the repressor of estrogen receptor activity (REA) enhances the response to estrogen in target tissues in vivo","volume":"25","author":"Park","year":"2005","journal-title":"Mol Cell Biol"},{"key":"2020071612015746000_B21","doi-asserted-by":"crossref","first-page":"3982","DOI":"10.1210\/en.2012-1044","article-title":"Uterine development and fertility are dependent on gene dosage of the nuclear receptor coregulator REA","volume":"153","author":"Park","year":"2012","journal-title":"Endocrinology"},{"key":"2020071612015746000_B22","doi-asserted-by":"crossref","first-page":"4336","DOI":"10.1210\/en.2011-1100","article-title":"Repressor of estrogen receptor activity (REA) is essential for mammary gland morphogenesis and functional activities: studies in conditional knockout mice","volume":"152","author":"Park","year":"2011","journal-title":"Endocrinology"},{"key":"2020071612015746000_B23","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1210\/en.2012-2026","article-title":"The coregulator, repressor of estrogen receptor activity (REA), is a crucial regulator of the timing and magnitude of uterine decidualization","volume":"154","author":"Zhao","year":"2013","journal-title":"Endocrinology"},{"key":"2020071612015746000_B24","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1210\/me.2014-1080","article-title":"Estrogen-induced CCN1 is critical for establishment of endometriosis-like lesions in mice","volume":"28","author":"Zhao","year":"2014","journal-title":"Mol Endocrinol"},{"key":"2020071612015746000_B25","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0015-0282(16)58381-2","article-title":"Elevated concentration and biologic activity of monocyte chemotactic protein-1 in the peritoneal fluid of patients with endometriosis","volume":"66","author":"Akoum","year":"1996","journal-title":"Fertil Steril"},{"key":"2020071612015746000_B26","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/S0015-0282(02)03333-2","article-title":"Induction of monocyte chemotactic protein-1 in peritoneal mesothelial and endometrial cells by oxidized low-density lipoprotein and peritoneal fluid from women with endometriosis","volume":"78","author":"Rong","year":"2002","journal-title":"Fertil Steril"},{"key":"2020071612015746000_B27","first-page":"1621","article-title":"Immunolocalization and regulation of the chemokine RANTES in human endometrial and endometriosis tissues and cells","volume":"82","author":"Hornung","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612015746000_B28","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0015-0282(00)01752-0","article-title":"Interleukin 1\u03b2, interleukin-6, and tumor necrosis factor-\u03b1 in endometriotic tissue and in endometrium","volume":"75","author":"Bergqvist","year":"2001","journal-title":"Fertil Steril"},{"key":"2020071612015746000_B29","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1095\/biolreprod.108.075069","article-title":"A botanical extract from channel flow inhibits cell proliferation, induces apoptosis, and suppresses CCL5 in human endometriotic stromal cells","volume":"81","author":"Wieser","year":"2009","journal-title":"Biol Reprod"},{"key":"2020071612015746000_B30","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1210\/jc.2002-020666","article-title":"Tumor necrosis factor-\u03b1-induced interleukin-8 (IL-8) expression in endometriotic stromal cells, probably through nuclear factor-\u03ba B activation: gonadotropin-releasing hormone agonist treatment reduced IL-8 expression","volume":"88","author":"Sakamoto","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612015746000_B31","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1093\/humupd\/dmu002","article-title":"The dynamics of nuclear receptors and nuclear receptor coregulators in the pathogenesis of endometriosis","volume":"20","author":"Han","year":"2014","journal-title":"Hum Reprod Update"},{"key":"2020071612015746000_B32","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1210\/er.2007-0012","article-title":"Nuclear receptor coregulators and human disease","volume":"28","author":"Lonard","year":"2007","journal-title":"Endocr Rev"},{"key":"2020071612015746000_B33","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1093\/humupd\/dmi034","article-title":"Aromatase and other steroidogenic genes in endometriosis: translational aspects","volume":"12","author":"Attar","year":"2006","journal-title":"Hum Reprod Update"},{"key":"2020071612015746000_B34","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1757-2215-5-31","article-title":"Dienogest increases the progesterone receptor isoform B\/A ratio in patients with ovarian endometriosis","volume":"5","author":"Hayashi","year":"2012","journal-title":"J Ovarian Res"},{"key":"2020071612015746000_B35","doi-asserted-by":"crossref","first-page":"700","DOI":"10.2353\/ajpath.2008.071128","article-title":"Endometrial-peritoneal interactions during endometriotic lesion establishment","volume":"173","author":"Hull","year":"2008","journal-title":"Am J Pathol"},{"key":"2020071612015746000_B36","doi-asserted-by":"crossref","first-page":"222ra216","DOI":"10.1126\/scitranslmed.3007988","article-title":"Molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation","volume":"6","author":"Beste","year":"2014","journal-title":"Sci Transl Med"},{"key":"2020071612015746000_B37","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/iub.1366","article-title":"Prohibitin 2: at a communications crossroads","volume":"67","author":"Bavelloni","year":"2015","journal-title":"IUBMB Life"},{"key":"2020071612015746000_B38","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/nm.2826","article-title":"A new isoform of steroid receptor coactivator-1 is crucial for pathogenic progression of endometriosis","volume":"18","author":"Han","year":"2012","journal-title":"Nat Med"},{"key":"2020071612015746000_B39","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1210\/en.2013-1947","article-title":"Kruppel-like factor 9 deficiency in uterine endometrial cells promotes ectopic lesion establishment associated with activated notch and hedgehog signaling in a mouse model of endometriosis","volume":"155","author":"Heard","year":"2014","journal-title":"Endocrinology"},{"key":"2020071612015746000_B40","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1093\/humrep\/17.7.1895","article-title":"Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis","volume":"17","author":"Anaf","year":"2002","journal-title":"Hum Reprod"},{"key":"2020071612015746000_B41","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1126\/science.1111445","article-title":"The pains of endometriosis","volume":"308","author":"Berkley","year":"2005","journal-title":"Science"},{"key":"2020071612015746000_B42","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.pain.2009.09.022","article-title":"Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation","volume":"147","author":"McAllister","year":"2009","journal-title":"Pain"},{"key":"2020071612015746000_B43","doi-asserted-by":"crossref","first-page":"4015","DOI":"10.1210\/en.2014-1086","article-title":"Estrogen receptor (ER) agonists differentially regulate neuroangiogenesis in peritoneal endometriosis via the repellent factor SLIT3","volume":"155","author":"Greaves","year":"2014","journal-title":"Endocrinology"},{"key":"2020071612015746000_B44","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1016\/j.ajpath.2015.04.012","article-title":"Estradiol is a critical mediator of macrophage-nerve cross talk in peritoneal endometriosis","volume":"185","author":"Greaves","year":"2015","journal-title":"Am J Pathol"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/157\/2\/900\/8999940\/endo0900.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/157\/2\/900\/8999940\/endo0900.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T04:37:28Z","timestamp":1692160648000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/157\/2\/900\/2423035"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,14]]},"references-count":44,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2016,2,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2015-1324","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,14]]}}}