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

Jung‐Yoon Yoo, Tae Hoon Kim, Jung‐Ho Shin, Ryan M. Marquardt, U. Mueller, Asgerally T. Fazleabas, Steven L. Young, Bruce A. Lessey, Ho‐Geun Yoon, Jae‐Wook Jeong
In: Research Square · 2020 · doi:10.21203/rs.3.rs-95903/v1 · W3148825889
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Abstract

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 ( 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 introduced Erbb2 ablation in Mig-6 d/d mice ( Mig-6 d/d Erbb2 d/d mice). The additional knockout of Erbb2 rescued all phenotypes seen in Mig-6 d/d mice including endometrial progesterone resistance, infertility, and endometriosis lesion development. Transcriptomic analysis showed that genes differentially expressed in Mig-6 d/d mice reverted to their normal expression amounts in Mig-6 d/d Erbb2 d/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.

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endometriosisinfertility

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