title: Multiple Beneficial Roles of Repressor of Estrogen Receptor Activity (REA) in Suppressing the Progression of Endometriosis.
abstract: 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(+/-)) grown in REA(+/-) 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.
authors.affiliation: Departments of Molecular and Integrative Physiology (Y.Z., Y.C., M.K.B., B.S.K.) and Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Gynecology and Obstetrics (Y.K.), The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; and Department of Obstetrics and Gynecology (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Yuechao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Departments of Molecular and Integrative Physiology (Y.Z., Y.C., M.K.B., B.S.K.) and Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Gynecology and Obstetrics (Y.K.), The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; and Department of Obstetrics and Gynecology (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Yiru
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Molecular and Integrative Physiology (Y.Z., Y.C., M.K.B., B.S.K.) and Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Gynecology and Obstetrics (Y.K.), The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; and Department of Obstetrics and Gynecology (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Ye
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Departments of Molecular and Integrative Physiology (Y.Z., Y.C., M.K.B., B.S.K.) and Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Gynecology and Obstetrics (Y.K.), The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; and Department of Obstetrics and Gynecology (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Milan K
authors.initials: MK
authors.lastname: Bagchi
authors.affiliation: Departments of Molecular and Integrative Physiology (Y.Z., Y.C., M.K.B., B.S.K.) and Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Gynecology and Obstetrics (Y.K.), The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; and Department of Obstetrics and Gynecology (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Taylor
authors.affiliation: Departments of Molecular and Integrative Physiology (Y.Z., Y.C., M.K.B., B.S.K.) and Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Gynecology and Obstetrics (Y.K.), The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; and Department of Obstetrics and Gynecology (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Departments of Molecular and Integrative Physiology (Y.Z., Y.C., M.K.B., B.S.K.) and Chemistry (J.A.K.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Gynecology and Obstetrics (Y.K.), The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; and Department of Obstetrics and Gynecology (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004715:Endometriosis / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics; D000091402:Prohibitins; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D016328:NF-kappa B; C000717331:PHB2 protein, human; D000091402:Prohibitins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D004958:Estradiol; D051546:Cyclooxygenase 2