Sang Jun Han,1 Sung Yun Jung,1,4 San-Pin Wu,1 Shannon M. Hawkins,2 Mi Jin Park,1 Satoru Kyo,3 Jun Qin,1,4 John P. Lydon,1 Sophia Y. Tsai,1 Ming-Jer Tsai,1 Francesco J. DeMayo,1,5 and Bert W. O’Malley1,5,*
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
2Departments of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA
3Department of Obstetrics and Gynecology, Kanazawa University, School of Medical Science, Ishikawa 920-8640, Japan
4Alkek Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
5These authors contributed equally to this work
*Correspondence: Bert W. O’Malley
Summary
Alterations in estrogen-mediated cellular signaling play an essential role in the pathogenesis of endometriosis. In addition to higher estrogen receptor (ER) β levels, enhanced ERβ activity was detected in endometriotic tissues, and the inhibition of enhanced ERβ activity by an ERβ-selective antagonist suppressed mouse ectopic lesion growth. Notably, gain of ERβ function stimulated the progression of endometriosis. As a mechanism to evade endogenous immune surveillance for cell survival, ERβ interacts with cellular apoptotic machinery in the cytoplasm to inhibit TNF-α-induced apoptosis. ERβ also interacts with components of the cytoplasmic inflammasome to increase interleukin-1β and thus enhance its cellular adhesion and proliferation properties. Furthermore, this gain of ERβ function enhances epithelial-mesenchymal transition signaling, thereby increasing the invasion activity of endometriotic tissues for establishment of ectopic lesions. Collectively, we reveal how endometrial tissue generated by retrograde menstruation can escape immune surveillance and develop into sustained ectopic lesions via gain of ERβ function.