The defining feature of endometriosis is that endometrial tissues are deposited and grown onto sites outside of the uterine cavity. The pathogenesis of endometriosis, however, remains controversial despite extensive research. Since the endometriosis has been known as an estrogen-dependent inflammatory disease, the 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 compared to the normal, 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 TNFα-induced apoptosis. ERβ also interacts with components of the cytoplasmic inflammasome to increase interleukin-1β and thus enhance its cellular adhesion and proliferation properties. Finally, the integration of the ERβ-regulated transcriptome and the ERβ-cistrome revealed that the gain of ERβ gene function directly enhances gene signatures of epithelial-mesenchymal transition and Reactive Oxygen Species in ectopic lesions in addition to cell cycle gene signature, thereby increasing the invasion and proliferation activities of endometriotic tissues for the establishment of ectopic lesions. Collectively, we reveal how endometrial tissue generated by retrograde menstruation can escape immune surveillance and develop into sustained ectopic lesions in part via gain of ERβ function.
27 Feb - 02 Mar 2018
Nuclear Receptors Conference