The roles of estrogen and estrogen receptors in gastrointestinal disease

Abstract

Estrogen is an important sex steroid hormone which serves an important role in the regulation of a number of biological functions, including regulating bone density, brain function, cholesterol mobilization, electrolyte balance, skin physiology, the cardiovascular system, the central nervous system and female reproductive organs. Estrogen exhibits various functions through binding to its specific receptors, estrogen receptor α, estrogen receptor β and G protein-coupled estrogen receptor 1. In recent years, researchers have demonstrated that estrogen and its receptors serve an important role in the gastrointestinal (GI) tract and contribute to the progression of a number of GI diseases, including gastroesophageal reflux, esophageal cancer, peptic ulcers, gastric cancer, inflammatory bowel disease, irritable bowel syndrome and colon cancer. The aim of this review is to provide an overview of estrogen and its receptors in GI disease, and highlight potential avenues for the prevention and treatment of GI diseases.

Keywords: G protein-coupled estrogen receptor 1; colon cancer; esophageal cancer; estrogen; estrogen receptor α; estrogen receptor β; estrogen receptors; gastric cancer; gastroesophageal reflux disease; inflammatory bowel disease; irritable bowel syndrome; peptic ulcer disease.

Figure 1.

Distribution of estrogen and ERs in the human body. ERs include two broad categories: Nuclear receptors, which includes ERα and ERβ and membrane receptors, which includes GPER1. ERα and ERβ are primarily expressed in the digestive system and the nervous system. ERβ, ERα and GPER1 are primarily expressed in bone tissue and the reproductive system. GPER1, G protein-coupled estrogen receptor 1; ER, estrogen receptor.

Figure 2.

Mechanisms of estrogen signaling. Direct pathway: When estrogen binds to the nuclear receptor, it forms an estrogen-receptor complex, which changes the conformation of the receptor, forming a dipolymer and exposing the DNA binding region. The complex enters the nucleus through the nuclear pore in the form of a dipolymer. Activated ERα/β can directly combine with ERE and subsequently interacts with the target gene or with other transcription factors, forming a complex, which promotes activity of regulatory proteins located at the promoter sites of target genes. This results in an increase in the mRNA expression and thus potentially protein expression levels of the target gene. Indirect pathway: GPER is rapidly activated by intracellular PCAF combining with estrogen-like substances. Activated GPER directly associates with CBP/P300 and interacts with the target gene or with other transcription factors, forming complexes such as the proto-oncogene Fos/jun and SP-1, which promotes activity of regulatory proteins located at the promoter sites of target genes. ER, estrogen receptor; GPER, G protein-coupled estrogen receptor; CBP/P300, transcription complex auxiliary activation factor; PCAF, P300/CBP-related factors; ERE, estrogen response element.

Figure 3.

Estrogen and the estrogen receptor-mediated signaling pathway. Estrogen is transported into the cell and combines with the estrogen receptor, forming a hormone-receptor complex. The combined complex enters the nucleus, and regulates the transcription process as described in Fig. 2. Nuclear estrogen receptor is a transcription factor that regulates the function of estrogen complexes and can modulate gene expression by interacting with other proteins and receptors.