Estrogen Receptors and Their Implications in Colorectal Carcinogenesis

Estrogen receptors (ERs) act by regulating transcriptional processes. The classical mechanism of ER action involves estrogen binding to receptors in the nucleus, after which the receptors dimerize and bind to specific response elements known as estrogen response elements (EREs) located in the promoters of target genes. However, ERs can also regulate gene expression without directly binding to DNA. This occurs through protein-protein interactions with other DNA-binding transcription factors in the nucleus. In addition, membrane-associated ERs mediate nongenomic actions of estrogens, which can lead both to altered functions of proteins in the cytoplasm and to regulation of gene expression. The latter two mechanisms of ER action enable a broader range of genes to be regulated than the range that can be regulated by the classical mechanism of ER action alone. This review surveys our knowledge about the molecular mechanism by which ERs regulate the expression of genes that do not contain EREs, and it gives examples of the ways in which the genomic and nongenomic actions of ERs on target genes converge. Genomic and nongenomic actions of ERs that do not depend on EREs influence the physiology of many target tissues, and thus, increasing our understanding of the molecular mechanisms behind these actions is highly relevant for the development of novel drugs that target specific receptor actions. Show more

Estrogens influence many physiological processes in mammals, including but not limited to reproduction, cardiovascular health, bone integrity, cognition, and behavior. Given this widespread role for estrogen in human physiology, it is not surprising that estrogen is also implicated in the development or progression of numerous diseases, which include but are not limited to various types of cancer (breast, ovarian, colorectal, prostate, endometrial), osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity. In many of these diseases, estrogen mediates its effects through the estrogen receptor (ER), which serves as the basis for many therapeutic interventions. This Review will describe diseases in which estrogen, through the ER, plays a role in the development or severity of disease. Show more

There is a growing amount of data suggesting that carcinomas of the right and left colon should be considered as different tumor entities. Using the data and analysis compiled in the German multicentered study "Colon/Rectum Cancer," we aimed to clarify whether the existing differences influence clinical and histological parameters, the perioperative course, and the survival of patients with right- vs left-sided colon cancer. During a 3-year period data on all patients with colon cancer were evaluated. Right- and left-sided cancers were compared regarding the following parameters: demographic factors, comorbidities, and histology. For patients who underwent elective surgery with curative intent, the perioperative course and survival were also analyzed. A total of 17,641 patients with colon carcinomas were included; 12,719 underwent curative surgery. Patients with right-sided colon cancer were significantly older, and predominantly women with a higher rate of comorbidities. Mortality was significantly higher for this group. Final pathology revealed a higher percentage of poorly differentiated and locally advanced tumors. Rate of synchronous distant metastases was comparable. However, hepatic and pulmonary metastases were more frequently found in left-sided, peritoneal carcinomatosis in right-sided carcinomas. Survival was significantly worse in patients with right-sided carcinomas on an adjusted multivariate model (odds ratio, 1.12). We found that right- and left-sided colon cancers are significantly different regarding epidemiological, clinical, and histological parameters. Patients with right-sided colon cancers have a worse prognosis. These discrepancies may be caused by genetic differences that account for distinct carcinogenesis and biological behavior. The impact of these findings on screening and therapy remains to be defined. Show more