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

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 () and Jae-Wook Jeong ()
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Jung-Yoon Yoo: Michigan State University, College of Human Medicine
Tae Hoon Kim: Michigan State University, College of Human Medicine
Jung-Ho Shin: Guro Hospital, Korea University Medical Center
Ryan M. Marquardt: Michigan State University, College of Human Medicine
Ulrich Müller: Johns Hopkins University School of Medicine
Asgerally T. Fazleabas: Michigan State University, College of Human Medicine
Steven L. Young: University of North Carolina
Bruce A. Lessey: Wake Forest Baptist Health
Ho-Geun Yoon: Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine
Jae-Wook Jeong: Michigan State University, College of Human Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28608-x

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