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

Authors :: Yoo JY
Kim TH
Shin JH
Marquardt RM
Müller U
Fazleabas AT
Young SL
Lessey BA
Yoon HG
Jeong JW
Source :: Nature communications [Nat Commun] 2022 Mar 01; Vol. 13 (1), pp. 1101. Date of Electronic Publication: 2022 Mar 01.
Publication Year :: 2022
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 (Pgr <superscript>cre/+</superscript> Mig-6 <superscript>f/f</superscript> ; Mig-6 <superscript>d/d</superscript> ). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6 <superscript>d/d</superscript> mice (Mig-6 <superscript>d/d</superscript> Erbb2 <superscript>d/d</superscript> mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6 <superscript>d/d</superscript> mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6 <superscript>d/d</superscript> mice revert to their normal expression in Mig-6 <superscript>d/d</superscript> Erbb2 <superscript>d/d</superscript> 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.<br /> (© 2022. The Author(s).)