As endometriosis is an estrogen-dependent inflammatory disease, estrogen/estrogen receptor (ER) signaling has an essential role in the pathogenesis of endometriosis. We revealed that cytoplasmic ER? interacts with the apoptosis machinery and inflammasome complex in endometriotic tissues to prevent apoptosis and stimulate cell proliferation activity, respectively. However, the function of nuclear ER? in the pathogenesis of endometriosis has not yet been elucidated. To fill this gap in the scientific knowledge, we have determined the endometriotic tissue-specific ER?-regulated transcriptome and ER?-cistrome by using a novel endometrium-specific ER? overexpression mouse model. Our new omics data provided three unique aspects of nuclear ER? function that drive endometriosis progression. 1) The increases in anti-apoptosis signaling in the endometrium is one of the critical drivers that promote the progression of endometriosis. Our omics data revealed that the ER?/Nuclear Factor of Activated T-cell 5 (NFAT5) complex directly downregulates the expression of N-Myc and STAT Interactor (NMI), which stimulates interferon (IFN)?-induced cell death signaling.
In Aim 1, we will investigate the role of NMI in IFN?-induced cell death signaling in the normal endometrium and then identify whether the ER?/NFAT5 complex downregulates the expression of NMI in endometriotic lesions to enhance endometriosis. Since epidermal growth factor receptor (EGFR) signaling is elevated in endometriotic tissue and involved in anti- apoptosis, we will also investigate the role of EGFR in the ER?/NFAT5-mediated suppression of NMI expression in endometriotic tissues. 2) The epithelial-mesenchymal transition (EMT) is a critical step for endometriosis. Our omics data showed that the ER?/Early Growth Response Protein 1 (EGR1) axis directly increased the expression of Fibrillin1 (FBN1), which is an activator of EMT, in ectopic lesions.
In Aim 2, we will define the role of FBN1 in endometriosis-associated EMT in ectopic lesions and then determine whether the ER?/EGR1 axis upregulates FBN1 gene expression in ectopic lesions to stimulate EMT in ectopic lesions. Since EGFR signaling also plays an essential role in EMT, the role of EGFR in ER?/EGR1 axis-mediated EMT will be investigated. 3) To establish endometriosis, angiogenesis is activated in ectopic lesions. However, the molecular mechanism of estrogen- induced angiogenesis in ectopic lesions has not been elucidated. Our data revealed that ER? elevated the expression of connective tissue growth factor (CTGF), which is the activator of hypoxia inducible factor 1a (HIF1A)-mediated angiogenesis, in ectopic lesions.
In Aim 3, we will define the role of CTGF in endometriosis- associated angiogenesis and then determine whether the ER?/HIF1A axis upregulates CTGF gene expression in ectopic lesions to stimulate angiogenesis. Since EGFR signaling also plays an essential role in angiogenesis, the role of EGFR in ER?/HIF1A axis-mediated angiogenesis will be investigated. Collectively, these three ER? gene networks will conceptionally advance our understanding of the molecular etiology of endometriosis and should provide new molecular therapeutic targets for alternative endometriosis therapies.
Endometriosis is a clinically significant but poorly understood condition that affects the productivity and well- being of millions of women in their reproductive years. Our proposed research project will define a new Estrogen Receptor ?-mediated gene network to understand the molecular mechanism of the inception and progression of endometriosis. This new conceptual advancement should provide new druggable targets to inhibit the survival and progression of endometriosis and reduce the side effects of current endometriosis treatments.
