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

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Authors: Jung-Yoon Yoo ; Tae Hoon Kim ; Jung-Ho Shin ; Ryan M Marquardt ; Ulrich Müller ; Asgerally T Fazleabas ; Steven L Young ; Bruce A Lessey ; Ho-Geun Yoon ; Jae-Wook Jeong

MeSH: Animals ; Endometriosis* / genetics ; Endometriosis* / metabolism ; Endometrium / abnormalities ; Endometrium / metabolism ; Female ; Infertility, Female* / genetics ; Infertility, Female* / metabolism ; Intracellular Signaling Peptides and Proteins* / deficiency ; Intracellular Signaling Peptides and Proteins* / metabolism ; Mice ; Progesterone / metabolism ; Receptor, ErbB-2* / genetics ; Receptor, ErbB-2* / metabolism ; Receptors, Progesterone / genetics ; Receptors, Progesterone / metabolism ; Uterine Diseases* / genetics ; Uterine Diseases* / metabolism

Abstract: 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 (Pgrcre/+Mig-6f/f; Mig-6d/d). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6d/d mice (Mig-6d/dErbb2d/d mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6d/d mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6d/d mice revert to their normal expression in Mig-6d/dErbb2d/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.