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

Abstract

Female subfertility is highly associated with endometriosis. Although the exact etiology of endometriosis-related infertility remains to be determined, endometrial progesterone resistance has recently been suggested as a crucial element in the development of endometrial diseases. Here, we report that MIG-6, a progesterone-induced gene, is downregulated in the endometrium of infertile women with endometriosis and in a non-human primate model of endometriosis. In an endometriosis mouse model with a fluorescent reporter used to identify lesions, an increase of endometriosis development and implantation failure were observed in mice with Mig-6 deficient endometrium compared to controls. MIG-6 is known to inhibit ERBB2, which we found overexpressed in the endometrium from uterine-specific Mig-6 knock-out mice (Pgrcre/+Mig-6f/f; Mig-6d/d). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduced Erbb2 ablation in Mig-6d/d mice (Mig-6d/dErbb2d/d mice). The additional knockout of Erbb2 rescued all phenotypes seen in Mig-6d/d mice including endometrial progesterone resistance, infertility, and endometriosis lesion development. Transcriptomic analysis showed that genes differentially expressed in Mig-6d/d mice reverted to their normal expression amounts in Mig-6d/dErbb2d/d mice. Together, our results demonstrate that MIG-6-induced ERBB2 overexpression causes endometrial progesterone resistance and a nonreceptive endometrium in endometriosis-related infertility and that ERBB2 targeting reverses these effects.