Loss of MIG-6 Results in Endometrial Progesterone Resistance and Endometriosis-Related Infertility through ERBB2 Overexpression.

Abstract

Introduction: Fertility problems are highly associated with endometriosis. Although the exact etiology of endometriosis-related infertility is unknown, endometrial progesterone resistance has recently been suggested as a crucial element in the development of endometrial diseases. MIG-6 acts as a key P4 signaling mediator in the endometrium of the human and mouse. Uterine-specifc Mig-6 knock-out mice (Pgrcre/+Mig-6f/f) are infertile due to non-receptive endometrium. We hypothesized that MIG-6 loss causes endometriosis-related infertility due to endometrial progesterone resistance. Methods: We examined MIG-6 levels in eutopic endometrium from infertile women with endometriosis. We utilized a non-human primate endometriosis model to track MIG-6 expression in eutopic endometrium through disease progression. To determine the efect of MIG-6 loss on endometriosis development, we surgically induced endometriosis with endometrium from control and Pgrcre/+Mig-6f/f mice. To investigate the efect of ERBB2 targeting on progesterone resistance and infertility, we introduced Erbb2 ablation in the Mig-6 knockout mice (Pgrcre/+Mig-6 f/f Erbb2 f/f). Results: The expression of MIG-6 mRNA and proteins were signifcantly reduced in eutopic endometrium of early secretory phase infertile women with endometriosis. Induction of endometriosis in a non-human primate model of endometriosis progressively reduced the expression of MIG6. Endometrial tissue from Pgrcre/+Mig-6f/f mice formed a signifcantly increased number of endometriotic lesions in the mouse compared to the control. ERBB2 overexpression was identifed in non-receptive endometrium from Pgrcre/+Mig-6f/f mice. Pgrcre/+Mig-6 f/f Erbb2 f/f double mutant mice reversed the endometrial progesterone resistance as well as all phenotypes including infertility and increased endometriosis development seen in Pgrcre/+Mig-6f/f mice. Remarkably, the transcriptomic analysis showed that altered genes in Mig-6d/d mice reverted to their normal expression levels in Mig-6d/dErbb2d/d mice. Conclusion: Together, our results demonstrate that MIG-6 loss causes progesterone resistance through ERBB2 overexpression in non-receptive endometrium of endometriosis-related infertility. Our results suggest that ERBB2 is a potential target for progesterone resistance and endometriosisrelated infertility.