![]() 2 ROLE OF ESTROGEN RECEPTORS (ERS) IN CRC PATHOGENESIS 2.1 The expression characteristics of ERβ and ERαĮstrogen signaling is mediated primarily by ERα and ERβ, which are encoded by estrogen receptor 1( ESR1) and estrogen receptor 2 ( ESR2) genes, respectively. We also outlined the use of some potential natural or synthetic compounds to target ER-mediated signaling in colon cancer cells to inhibit their proliferation and progression. In this review, we discuss the roles of estrogen receptors and their multiple molecular targets in CRC pathogenesis. A deep understanding of the underlying molecular mechanisms of estrogen and its receptors may provide prospects for improved CRC management. 6 Estrogens and their receptors show either positive or negative roles in the pathogenesis of CRC. 1, 5 By cross talking with other signaling pathways such as RAS/RAF/ERK1/2 and EGFR pathways, GPER may also regulate colonic mobility. 3 Furthermore, GPER can positively regulates cell proliferation, migration and invasion of colon cancer cells, thus, promoting the pathogenesis and progression of CRC. Moreover, deficiency of estrogen receptor α (ERα) along with ERβ modulates colon neoplastic transformation and abnormal mucosal formation in an APC-dependent tumourigenesis model. 3, 4 A significantly lower level of ERβ was noted in CRC patients with advanced clinical stages (stages III & IV) when compared with early stages (stages I & II) patients. 4 Thus, downregulation of the ERβ receptor in intestinal mucosa may result in the development of CRC. ![]() 3 Expression of ERβ in the intestinal crypts may protect the body from developing cancer. 1 ERβ, the most prominent among all the estrogen receptor, acts as a tumor suppressor in CRC along with prognostic significance. 2 The functionality of estrogens in cancer is mediated by the nuclear estrogen receptors α and β (ERα and ERβ), as well as by the membrane-bound G protein-coupled estrogen receptor (GPER). nuclear or membrane) receptors are often controversial in colorectal cancer (CRC) genesis. ![]() 1, 2 In general, estrogen acts as a cancer-protective hormone through its anti-inflammatory activities however, the roles of individual estrogen (i.e. Also, we reviewed the actions of naturally occurring and synthetic compounds, which have a protective role against CRC development by acting as ER agonist.Įstrogens are known to play essential roles in the initiation and progression of multiple tumor types, especially tumors of hormonally regulated tissues such as the breast, endometrium and ovary. In this study, we report the most recent pre-clinical and experimental evidences related to ERs in CRC development. Furthermore, using synthetic or natural compounds as ER agonists may induce estrogen-mediated anti-cancer activities against colon cancer. Thus, a better understanding of the underlying mechanisms of estrogen and its receptors in CRC pathogenesis could provide a new horizon for effective therapeutic development. ERβ may exert the anti-tumor effect through selective activation of pro-apoptotic signaling, increasing DNA repair, inhibiting expression of oncogenes, regulating cell cycle progression, and also by changing the micro-RNA pool and DNA-methylation. ![]() ERβ, the predominant estrogen receptor expressed in both normal and non-malignant colonic epithelium, has protective roles in colon carcinogenesis. ERβ and ERα are responsible for the genomic actions of estrogens, whereas the other receptor, such as G protein-coupled estrogen receptor (GPER) regulates rapid non-genomic actions, which lead to secondary gene expression changes in cells. Estrogen receptors such as ERα and ERβ activate intracellular signaling cascades followed by binding to estrogen, resulting in important changes in cellular behaviors. Estrogens have been implicated in the pathogenesis of various cancer types, including colorectal carcinoma (CRC).
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