Preclinical study reveals that ERBB2 ablation rescues endometrial progesterone resistance and infertility caused by MIG-6 deficiency in mouse models, highlighting a potential therapeutic target.
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 cre/+ Mig-6 f/f ; Mig-6 d/d ). To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb2 ablation in Mig-6 d/d mice ( Mig-6 d/d Erbb2 d/d mice). The additional knockout of Erbb2 rescues all phenotypes seen in Mig-6 d/d mice. Transcriptomic analysis shows that genes differentially expressed in Mig-6 d/d mice revert to their normal expression in Mig-6 d/d Erbb2 d/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.
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Yoo et al. (2022) studied this question.
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