Multiple beneficial roles of repressor of estrogen receptor activity (REA) in suppressing the progression of endometriosis

Yuechao Zhao, Yiru Chen, Ye Kuang, Milan K. Bagchi, Robert N. Taylor, John A. Katzenellenbogen, Benita S. Katzenellenbogen

Research output: Contribution to journalArticle

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, weused 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.

Original languageEnglish (US)
Pages (from-to)900-912
Number of pages13
JournalEndocrinology
Volume157
Issue number2
DOIs
StatePublished - Feb 2016

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Endometriosis
Estrogen Receptors
Tissue Donors
Estradiol Receptors
Choristoma
Pelvic Pain
Gene Dosage
NF-kappa B
Cyclooxygenase 2
Stromal Cells
Endometrium
Fertility
Cell Cycle
Estrogens
Cytokines
Inflammation
Neurons
Therapeutics

ASJC Scopus subject areas

  • Endocrinology

Cite this

Multiple beneficial roles of repressor of estrogen receptor activity (REA) in suppressing the progression of endometriosis. / Zhao, Yuechao; Chen, Yiru; Kuang, Ye; Bagchi, Milan K.; Taylor, Robert N.; Katzenellenbogen, John A.; Katzenellenbogen, Benita S.

In: Endocrinology, Vol. 157, No. 2, 02.2016, p. 900-912.

Research output: Contribution to journalArticle

Zhao, Yuechao ; Chen, Yiru ; Kuang, Ye ; Bagchi, Milan K. ; Taylor, Robert N. ; Katzenellenbogen, John A. ; Katzenellenbogen, Benita S. / Multiple beneficial roles of repressor of estrogen receptor activity (REA) in suppressing the progression of endometriosis. In: Endocrinology. 2016 ; Vol. 157, No. 2. pp. 900-912.
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