Loss of MIG-6 results in endometrial progesterone resistance via ERBB2

Female subfertility is highly associated with endometriosis. Endometrial progesterone resistance is suggested as a crucial element in the development of endometrial diseases. We report that MIG-6 is downregulated in the endometrium of infertile women with endometriosis and in a non-human primate model of endometriosis. We find ERBB2 overexpression in the endometrium of uterine-specific Mig-6 knockout mice (Pgr(cre/+)Mig-6(f/f); Mig-6(d/d)). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6(d/d) mice (Mig-6(d/d)Erbb2(d/d) mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6(d/d) mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6(d/d) mice revert to their normal expression in Mig-6(d/d)Erbb2(d/d) mice. Together, our results demonstrate that ERBB2 overexpression in endometrium with MIG-6 deficiency causes endometrial progesterone resistance and a nonreceptive endometrium in endometriosis-related infertility, and ERBB2 targeting reverses these effects.