Inhibition of epidermal growth factor receptor restores decidualization markers in stromal fibroblasts from women with endometriosis

Abstract

Purpose Decidualization comprises specific biochemical and morphological changes in uterine endometrium essential for establishment of pregnancy. This process is abnormal in women with endometriosis, a disorder in which endometrial-like tissue is present outside the uterus. The aim of this study was to restore cAMP-induced decidualization marker expression in endometrial stromal fibroblasts from women with endometriosis by using chemical inhibitors to PI3K/AKT/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) signaling pathways in vitro. Methods Endometrial stromal fibroblasts (eSF) from women with (eSFendo) and without (eSFnon-endo) endometriosis were treated with inhibitors to EGFR tyrosine kinase (gefitinib), mTOR (rapamycin) and MAPK kinase 1/2 (MEK1/2) (UO126) during 8-bromoadenosine 3′,5′-cyclic monophosphate (8-br-cAMP)–stimulated decidualization. Decidualization was assessed by evaluating expression of insulin growth factor binding protein 1 (IGFBP1), prolactin (PRL) and forkhead box protein O1A (FOXO1A) by quantitative real-time PCR. Results Gefitinib restored expression of decidualization markers in eSFendo to levels consistent with those in eSFnon-endo. Elevated levels of phosphorylated mTOR in eSFendo were reduced to levels found in eSFnon-endo, by gefitinib during treatment with 8-br-cAMP. Additional gene expression analyses suggested dysregulation of EGFR negative feedback regulators in eSFendo. Conclusions Results implicate EGFR signaling as an underlying cause for aberrant cAMP-induced decidualization in women with endometriosis, and provide a potential target for management of infertility associated with the disease. The reduction of p-mTOR levels in eSFendo during 8-br-cAMP treatment suggests cooperation between EGR and protein kinase A signaling in the regulation of mTOR in eSF.

Steroid hormones regulate genome-wide epigenetic programming and gene transcription in human endometrial cells with marked aberrancies in endometriosis

“…Signaling through EGFR is a key pathway in eSF response to E 2 , and constitutive activation of EGFR in eSF from women with endometriosis has been reported [70]. Inhibition of EGFR in eSF from women with disease restores decidualization markers [71], underscoring the complexity of the interplay between E 2 and P 4 signaling in eSF in endometrium of women with endometriosis. The data overall support phosphorylation of ERα in eSF treated with E 2 may contribute, in part, to differential DNA methylation signatures and gene expression profiles observed in E 2 versus E 2 +P 4 in women without and with disease, which remains to be proven experimentally.…”

Global Transcriptome Abnormalities of the Eutopic Endometrium From Women With Adenomyosis

“…The mTOR is a serine/threonine protein kinase that regulates cell proliferation and survival, which is upregulated in endometriosis. 37,38 Dysregulation of mTOR is noted in human malignancies inhibitors of mTOR are currently in development and clinical investigation as novel anticancer agents. [39][40][41][42] Induction of apoptoptic pathways may be a therapeutic target for endometrial dysfunction in women with symptomatic adenomyosis.…”

Complications during pregnancy and delivery in women with untreated rectovaginal deep infiltrating endometriosis

“…Pregnancy complications accompanying preexisting endometriosis may be explained by some pathogenic mechanisms, such as endometriosis-related chronic inflammation (8), presence of adhesions and their mechanical implications (9), and invasion of decidualized ectopic endometrium in to the vessels wall (10,11). It has also been suggested that pregnancy complications may differ on the basis of the type of endometriotic lesion (6,12).…”