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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen is widely applied as an antiestrogenic agent for adjuvant therapy in the treatment of breast cancer, while its estrogen-agonistic activity occasionally causes proliferative disorders or carcinogenesis at other sites, such as the uterus. We reported that estrogen activates telomerase in breast and endometrial cancer cells. The present study examines the effects of tamoxifen on the gene expression of human telomerase reverse transcriptase (hTERT) in breast and endometrial cancer cells. Tamoxifen inhibited the cell growth of MCF-7 cells, as well as hTERT mRNA expression in the presence of estrogen (E2), antagonizing the E2 effects. In contrast, tamoxifen stimulated the growth of Ishikawa cells and activated hTERT mRNA expression in the absence or presence of E2, exhibiting estrogen-agonistic action. Transient expression assays revealed that these actions of tamoxifen are achieved by transcriptional regulation of the hTERT promoter. An estrogen responsive element (ERE) in the hTERT 5' regulatory region was partly responsible for both the E2-antagonistic and -agonistic actions of tamoxifen. Tamoxifen activated the MAP kinase cascade in Ishikawa cells, but not in MCF-7 cells, and the activation of hTERT mRNA expression was effectively blocked by MEK inhibitor, suggesting that the MAP kinase pathway is involved in the tamoxifen-induced activation of hTERT. These findings indicate that tamoxifen regulates hTERT expression in a cell-type specific manner. Tamoxifen-induced activation of hTERT may be one component of estrogen agonistic function of tamoxifen that is involved in endometrial carcinogenesis induced by this agent.
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PMID:Tamoxifen regulates human telomerase reverse transcriptase (hTERT) gene expression differently in breast and endometrial cancer cells. 1203 53

Tamoxifen is an estrogen receptor (ER)-antagonist that is widely used for the treatment of breast cancer, although it increases the risk of endometrial cancer. The mechanism mediating the stimulatory effect of tamoxifen on endometrial cancer is presently unknown. In this study we examined the effects of tamoxifen on Ishikawa 3H-12 endometrial cancer cells and MCF-7 breast cancer cells. Ishikawa cell growth was stimulated by 4-hydroxytamoxifen and accompanied by increased transcriptional activity of the endogenous ER. These stimulatory effects did not occur in MCF-7 cells. The relative transcriptional activity of the activation function (AF) 1 domain of ERalpha compared with that of the AF2 domain was 4-fold higher in Ishikawa cells than in MCF-7 cells. Mitogen-activated protein (MAP) kinase, which stimulates the transcriptional activity of AF1, was constitutively activated in Ishikawa cells, but not in MCF-7 cells. These observations suggest that the constitutively activated MAP kinase-signaling pathway in Ishikawa cells enhances the transcriptional activity of ERalpha via the AF1 domain. This ERalpha activation pathway may be involved in the stimulatory effect of tamoxifen on the development and/or progression of endometrial cancer.
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PMID:Estrogen receptor-mediated effects of tamoxifen on human endometrial cancer cells. 1208 71

Estrogen and its receptor play important roles in genesis and malignant progression of estrogen-dependent cancers, together with various growth factors. Functional cross-talk between estrogen-signaling and growth factor-mediated signaling pathways has been reported. Firstly, we show an example of the cross-talk that may alter the effect of antagonist on the breast and endometrial cancer cell growth. Our observations suggest that the constitutively activated MAP kinase-signaling pathway in endometrial cancer cells might enhance the transcriptional activity of ERalpha via phosphorylation of AF-1 domain. This mechanism may cause the growth stimulative effect of tamoxifen on the endometrium. Secondly, we show our recent study for comprehensive understanding of estrogen-signaling pathway using cDNA microarray. According to the results of the expression profiling of estrogen-responsive genes in ER-positive breast cancer cells using large-scale cDNA microarray, the custom-made cDNA microarray, on which only estrogen-responsive genes were loaded, was produced. Using this microarray consisting of the narrowed gene subset, we analyzed estrogen responsiveness of various cell lines and effect of estrogen antagonists. Aim of this study is not only to address the molecular mechanisms of estrogen-dependent growth of breast cancer, but also to develop the new diagnostic tools for responsiveness to hormone therapy of primary breast cancer patients. Finally, in order to understand the local tumor biology including stroma-cancer interaction, we recently developed the new analytical system using ERE-GFP introduced into breast cancer cells. Several observations indicated that these reporter cells were useful for assessment of stimulative effects of stroma cells adjacent to breast cancer on the estrogen-signaling pathway. These studies may provide not only new clues for elucidation of the molecular mechanisms of estrogen-dependent growth of breast cancer, but also assessment of anti-estrogen responses of individual breast cancer for patient-tailored hormone therapy.
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PMID:Estrogen and growth factor signaling pathway: basic approaches for clinical application. 1462 41

Deregulated signaling via the phosphatidylinositol 3-kinase (PI3K) pathway is common in many types of cancer, but its clinicopathological significance in endometrial cancer remains unclear. In the present study, we examined the status of the PI3K signaling pathway, especially in relation to PTEN and PIK3CA status, in endometrioid-type endometrial cancer. The immunohistochemical analysis revealed a high level of phosphorylated (p)-AKT expression, which is a hallmark of activated PI3K signaling, in approximately 60% of endometrial cancers. There was no correlation between p-AKT expression and clinicopathological characteristics, such as International Federation of Gynecology and Obstetrics stage, tumor grade, and myometrial invasion. Unexpectedly, a high level of p-AKT expression occurred independently of the presence of PTEN or PIK3CA mutations. Furthermore, p-AKT expression did not correlate with the expression of potential downstream targets, including p-mTOR and p-FOXO1/3a. In turn, p-AKT expression was strongly associated with extracellular-regulated kinase 1/2 expression (P = 0.0031), which is representative of the activated RAS-MAP kinase pathway. Kaplan-Meier analysis suggested that low p-AKT expression was associated with low rates of relapse-free survival, although the difference was not statistically significant, indicating that AKT activation does not confer worse prognosis. The present study demonstrates the presence of complex signaling pathways that might mask the conventional tumorigenic PTEN-PI3K-AKT-mTOR pathway, and strongly suggests a close association between the extracellular-regulated kinase and PI3K pathways in this tumor type.
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PMID:Concomitant activation of AKT with extracellular-regulated kinase 1/2 occurs independently of PTEN or PIK3CA mutations in endometrial cancer and may be associated with favorable prognosiss. 1792 77

Uterine corpus endometrial carcinoma (UCEC) is a common malignancy in the female reproductive system, associated with high morbidity and mortality. Despite the high prevalence of UCEC, molecular understanding of uterine endothelium tumorigenesis remains poorly understood. In this study, we reported that transcription factor 21 (TCF21) inhibits cancer cell proliferation and invasion following overexpression, in vitro and in vivo. Moreover, in response to hypoxia, TCF21 is highly expressed in UCEC cells carrying wild-type p53, and is transcriptional target of p53. We observed that TCF21 interferes with the MAP kinase pathway, which is supported by a substantially reduced level of phosphorylated mitogen-activated protein kinase 1 (MAPK1 or ERK) in cells expressing a higher level of TCF21. Furthermore, we identified the specific region of TCF21 that is responsible for its interaction with mitogen-activated protein kinase 1 (MEK) and a subsequently reduced activity of ERK. Using molecular docking and mutagenesis analysis, we validated a special domain of TCF21, which can reduce the activity of the MAPK pathway and inhibit uterine endothelium tumor cell growth in vitro. Overall, our study determined that TCF21, a hypoxia-driven p53 target, functions as a tumor suppressor in UCEC and presents as a therapeutic target for tumor treatment.
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PMID:A Novel Target of p53, TCF21, Can Respond to Hypoxia by MAPK Pathway Inactivation in Uterine Corpus Endometrial Carcinoma. 2960 30