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.
Highlights
Female subfertility is highly associated with endometriosis
As measured by RT-qPCR, mitogen inducible gene 6 (MIG-6) expression in the human endometrium was significantly higher in the early secretory phase of the menstrual cycle than in the proliferative (p < 0.0001), mid secretory (p = 0.0106), and late secretory phase (p = 0.0029) (Fig. 1a), suggesting that MIG-6 is a P4-induced gene in the human endometrium as has been demonstrated in the mouse[20]
RT-qPCR and immunohistochemistry showed that amounts of MIG-6 mRNA (p = 0.0079) and protein (p < 0.0001) were significantly lower in the eutopic endometrium of infertile women with endometriosis compared to controls in the early secretory phase (Fig. 1, a–c)
Summary
Female subfertility is highly associated with endometriosis. Endometrial progesterone resistance is suggested as a crucial element in the development of endometrial diseases. To investigate the effect of ERBB2 targeting on endometrial progesterone resistance, fertility, and endometriosis, we introduce Erbb[2] ablation in Mig-6d/d mice (Mig-6d/dErbb2d/d mice). 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. P4-induced molecular changes in the eutopic (intrauterine) endometrial tissue of women with endometriosis are either blunted or undetectable[10–12]. Many P4-induced molecular changes in the eutopic endometrial tissue of women with endometriosis are either blunted or dysregulated[17,18], but an impaired P4 response is seen in the endometrium of women with endometriosis[4–6,10]. We use uterine-specific Mig-6 knock-out mice to demonstrate that MIG-6 loss results in endometrial progesterone resistance via erb-b2 receptor tyrosine kinase 2 (ERBB2; known as CD340, proto-oncogene Neu, or HER2). Our findings provide insight into the etiology of female infertility and a molecular framework useful for the design of therapeutic strategies
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