Implications of estrogen and its receptors in colorectal carcinoma

Abstract

Estrogens have been implicated in the pathogenesis of various cancer types, including colorectal carcinoma (CRC). Estrogen receptors such as ERα and ERβ activate intracellular signaling cascades followed by binding to estrogen, resulting in important changes in cellular behaviors. The nuclear estrogen receptors, i.e. 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. ERβ, the predominant estrogen receptor expressed in both normal and non-malignant colonic epithelium, has protective roles in colon carcinogenesis. 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. 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. Furthermore, using synthetic or natural compounds as ER agonists may induce estrogen-mediated anti-cancer activities against colon cancer. In this study, we report the most recent pre-clinical and experimental evidences related to ERs in CRC development. Also, we reviewed the actions of naturally occurring and synthetic compounds, which have a protective role against CRC development by acting as ER agonist.

Keywords: chemotherapy, targeted therapy; colorectal carcinoma; estrogen; estrogen receptors.

FIGURE 1

Roles of ERβin CRC pathogenesis. Upon binding to its ligand ERβ becomes activated and transcriptionally upregulates downstream target genes such as FOXO3a. The target genes carry ERβ binding elements such as ERE or AP1. The activated FOXO3a in turn transcriptionally upregulates PUMA, p21, and p27. ERβ also inhibits expression of genes such as c‐Myc and p45Skp2. Moreover, some of the EMT and metastasis genes, such as β‐catenin, Slug and Twist, are inhibited by ERβ.

FIGURE 2

Molecular mechanism for ERβ‐mediated anti‐tumorigenic activity in CRC. ERβ mediates its anti‐tumourigenic property by inducing prompt DNA repair capacity, increasing apoptosis signaling, enhancing anti‐inflammatory response and by reducing tumor metastasis.

FIGURE 3

Signaling pathways modulated by G protein‐coupled estrogen receptor in colon cancer cells. Upon binding of ligands, GPER starts a signaling cascade which ultimately results in target genes expression to maintain various properties of colon cancer cells.