4 in 1975 to 32 in 2012 and the total morbidity increased from 2

4 in 1975 to 3.2 in 2012 and the total morbidity increased from 229 to 2092.[4] selleck kinase inhibitor The incidence of endometrial cancer is

likely to continue to increase based on these recent trends. Discovering the causes of the increase and establishment of prophylactic measures and new therapeutic strategies requires an improved understanding of the carcinogenic mechanisms of endometrial cancer. Environmental factors, including estrogen, an abnormal mismatch repair (MMR) system, genetic abnormalities, and aberrant methylation of DNA and microRNA, are currently proposed as major mechanisms of carcinogenesis in endometrial cancer. Endometrial cancer is defined as type I or II based on clinicopathological properties. Type I endometrial cancer more commonly develops in

premenopausal or perimenopausal women and occurs in an estrogen-dependent manner via atypical endometrial hyperplasia. The tumor is positive for the estrogen receptor and progesterone receptor, shows well-differentiated endometrioid adenocarcinoma, has a lower frequency of lymph node metastasis, shows little muscular invasion, and often has a relatively favorable prognosis. In contrast, type II endometrial cancer GDC-0199 in vivo tends to develop in postmenopausal women in an estrogen-independent manner, and is thought to be due to de novo carcinogenesis that develops directly from the normal endometrium, rather than via endometrial hyperplasia or undiagnosed precancerous lesions. The tissue type is specific, including extremely poorly differentiated endometrioid adenocarcinoma Succinyl-CoA and serous adenocarcinoma, and the prognosis is often poor. This review focuses on the mechanisms of carcinogenesis in endometrial cancer that have recently emerged. Estrogen is a steroid hormone that promotes the development of female

genitalia, including the endometrium, vagina, vulva and mammary gland. Estrogen passes through the cell membrane and binds to estrogen receptor (ER) in the cytoplasm. ER forms dimers and regulates gene expression via estrogen response elements in promoter regions of target genes. ER has ligand- and DNA-binding domains, and ligand-independent activation function (AF)-1 and ligand-dependent AF-2 transcriptional activation domains.[5] The balance of transcriptional activation domains varies among tissues, with dominance of AF-2 in mammary gland cells and AF-1 in endometrial cells.[6, 7] Miyamoto et‚ÄČal.[8] suggested that mismatch repair (MMR) deficiency was the most important abnormality in early-stage endometrial cancer, and examined the correlation between MMR and estrogen. Expression of hMLH1 and hMSH2, which are important MMR proteins, was examined by immunostaining and showed a strong positive correlation with blood estrogen. MMR activity in endometrial epithelial cells in vitro also showed a dose-dependent increase with higher estrogen levels.

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