UMLS:C0476089 - FACTA Search

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

Endometrial cancer is the most common gynecological cancer in Western industrialized countries. Cables, a cyclin-dependent kinase binding protein, plays a role in proliferation and/or differentiation. Cables mutant mice are viable, but develop endometrial hyperplasia and carcinoma in situ at a young age. Exposure to chronic low levels of estrogen results in development of endometrial cancer, similar to that observed in the postmenopausal female. In vitro and in vivo studies demonstrate that levels of Cables mRNA in benign human endometrial epithelium are up-regulated by progesterone and down-regulated by estrogen. Furthermore, nuclear immunostaining for Cables is lost in a high percentage of cases of human endometrial hyperplasia and adenocarcinoma, which are likely the product of unopposed estrogen. The loss of Cables immunostaining in the human endometrial cancer samples correlates with a marked decrease in Cables mRNA. Ectopic expression of Cables in human endometrial cells dramatically slows cell proliferation. Collectively, these data provide evidence that Cables is hormonally regulated and is involved in regulating endometrial cell proliferation. In addition, loss or suppression of Cables may be an early step in the development of endometrial cancer.
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PMID:Loss of cables, a cyclin-dependent kinase regulatory protein, is associated with the development of endometrial hyperplasia and endometrial cancer. 1472 25

A considerable amount of evidence indicates that Ras signaling contributes to the development of endometrial cancer. We previously demonstrated that endometrial cancer cells carrying oncogenic [(12)Val]K-ras were susceptible to apoptosis. The present study examined the role of K-and H-Ras in the induction of apoptosis using rat endometrial cells (RENT4 cells). We found that constitutively activated K-Ras promoted apoptotic cell death, whereas the H-Ras mutant rescued rat endometrial cells from apoptosis. Expression of a constitutively active form of Raf-1 (Raf-CAAX) promoted apoptosis, whereas expression of a constitutively active catalytic subunit of phosphoinositide 3-kinase, p110K227E, allowed cells to escape from apoptosis. Moreover, inhibition of the MEK-MAPK pathway by the specific inhibitor, UO126, rescued the cells from apoptosis, whereas the inhibition of phosphoinositide 3-kinase by its specific inhibitor, LY294002, promoted apoptosis in RENT4 cells expressing activated K-Ras. However, both inhibitors promoted apoptosis in RENT4 cells expressing activated H-Ras. This difference in the regulation of apoptosis by the MEK inhibitor between K-Ras- and H-Ras-expressing cells depended on the interaction of effector proteins downstream of each Ras isoform. Finally, to elucidate the role of downstream K-Ras signal pathways, we generated K-Ras effector domain mutants (K12V35S, K12V40C). We examined the incidence of apoptotic cell death induced by the K-Ras effector domain mutants (K12V35S, K12V40C). The relative ratio of phospho-MAPK to phospho-Akt compared with that of mock cells was higher in K12V35S cells than in K12V40C cells. Ectopic expression of K12V35S protein increased the proportion of apoptotic cells, and in turn, the expression of K12V40C protein decreased compared with the expression of K12V protein without the effector domain mutant. These results demonstrate that K- and H-Ras-mediated signaling pathways exert distinct effects on apoptosis and that K-Ras downstream Raf/MEK/MAPK pathway is required for the induction of apoptosis in endometrial cells. Coordination of the two pathways contributes to endometrial cell survival.
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PMID:K-Ras and H-Ras activation promote distinct consequences on endometrial cell survival. 1508 91

Overexpression of the lipogenic enzyme fatty acid synthase (FAS) is a common molecular feature in subsets of sex-steroid-related tumors including endometrium and breast carcinomas that are associated with poor prognosis. Pharmacological inhibition of tumor-associated FAS hyperactivity is under investigation as a chemotherapeutic target. We examined the effects of the mycotoxin cerulenin (a covalent FAS inactivator), and the novel small compound C75 (a slow-binding FAS inhibitor) on estradiol (E2)- and tamoxifen (TAM)-stimulated ER-driven molecular responses in Ishikawa cells, an in vitro model of well-differentiated human endometrial carcinoma. We evaluated the effects of FAS inhibition on E2- and TAM-induced estrogen receptor (ER) transcriptional activity by using transient cotransfection assays with an estrogen-response element reporter construct (ERE-Luciferase). Antiestrogenic effects of cerulenin and C75 were observed by dose-dependent inhibition of E2-stimulated ERE-dependent transcription, whereas FAS inhibitors did not significantly increase the levels of ERE transcriptional activity in the absence of E2. Moreover, pharmacological blockade of FAS activity completely abolished TAM-stimulated ERE activity. To address the reliability of transient transfection assays, the effects of FAS inhibitors on E2-inducible gene products were evaluated. FAS blockade induced a dose-dependent decrease in E2-inducible alkaline phosphatase activity. E2-stimulated accumulation of progesterone receptor (PR) and HER-2/neu oncogene was abolished in the presence of FAS blockers. FAS inhibition also resulted in a marked downregulation of E2-stimulated ERalpha expression, and noticeably impaired E2-induced ERalpha nuclear accumulation. A dose-dependent decrease in cell proliferation and cell viability was observed after FAS blockade. A Cell Death ELISA, detecting DNA fragmentation, demonstrated that FAS inhibitors stimulated apoptosis of Ishikawa cells. The analysis of critical E2- and TAM-related cell cycle proteins revealed an increase of both the expression and the nuclear accumulation of cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27Kip1 following FAS inhibition. To rule out non-FAS cerulenin- and C75-related effects, we finally monitored ER signaling after silencing of FAS gene expression using the highly sequence-specific mechanism of RNA interference (RNAi). The concentrations of E2 and TAM inducing half-maximal ERE activity (EC50) dramatically increased (>100 times) in FAS RNAi-transfected Ishikawa cells. Moreover, depletion of FAS by RNAi also caused loss of ERalpha expression, downregulation of PR, and accumulation of p21WAF1/CIP1 and p27Kip1 in E2-stimulated Ishikawa cells. If chemically stable FAS inhibitors or cell-selective vector systems able to deliver RNAi targeting FAS gene demonstrate systemic anticancer effects in vivo, our results render FAS as a novel target for the prevention and treatment of endometrial carcinoma.
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PMID:Inhibition of tumor-associated fatty acid synthase activity antagonizes estradiol- and tamoxifen-induced agonist transactivation of estrogen receptor (ER) in human endometrial adenocarcinoma cells. 1509 77

p27 is a cyclin-dependent kinase (CDK) inhibitor whose specific late G(1) destruction allows progression of the cell across the G(1)/S boundary. The protein is ubiquitinated by S-phase kinase-interacting protein-2 (Skp2) following its specific phosphorylation, and is subsequently degraded by the 26s proteasome. There is a direct relationship between low level of p27 and rapid proliferation occurring in several benign states and in many malignancies. In the glandular cells of the normal endometrium, the level of p27 is exceedingly low during the proliferative phase, whereas it is markedly increased during the secretory phase. The expression of p27 in endometrial carcinoma is very low but has been found to increase following treatment with progesterone. However, estrogen exposure is considered as a major risk factor in developing endometrial cancer. The implications of the high dose of estrogen and progesterone induced during IVF treatment are still unknown. We have examined the expression of p27 and Skp2 as well as of Ki67 proliferation marker by using endometrial extracts and cells from normal endometrium, from ovarian hyperstimulated patients, and from endometrial carcinoma patients. The expression of p27, Skp2 and Ki67 was found to be similar in both normal secretory endometrium and endometrium from ovarian hyperstimulated patients. In striking contrast, p27 is significantly lower while Skp2 and Ki67 are significantly higher in the endometrial carcinoma and in endometrium from the proliferative phase compared with their normal secretory counterpart tissue.
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PMID:Decreased level of the cell cycle regulator p27 and increased level of its ubiquitin ligase Skp2 in endometrial carcinoma but not in normal secretory or in hyperstimulated endometrium. 1522 Apr 66

The recently described gene, RAB32, is a ras proto-oncogene family member that encodes an A-kinase-anchoring protein. RAB32 has been found to be frequently hypermethylated in microsatellite instability-high (MSI-H) colon cancers. We sought to determine the prevalence of RAB32 hypermethylation in gastric and endometrial adenocarcinomas, the 2 other major tumor types in which MSI-H is common. Moreover, we delineated the association of RAB32 hypermethylation with microsatellite instability (MSI) and hMLH1 hypermethylation. MSI status and hypermethylation of the RAB32 and hMLH1 genes were studied in paired primary normal and tumor tissues from 48 patients with gastric cancer. An additional 80 endometrial cancer patients were studied for RAB32 methylation and MSI status. Thirteen (27%) of 48 gastric cancers demonstrated evidence of RAB32 hypermethylation. MSI status was determined in 46 of the tumors, with 7 (100%) of 7 MSI-H tumors, 1 (33%) of 3 MSI-low (MSI-L) tumors and 4 (11%) of 36 microsatellite-stable (MSS) tumors found to harbor RAB32 hypermethylation. RAB32 methylation was significantly associated with intestinal type histology and concomitant hMLH1 hypermethylation in gastric cancer. In contrast, RAB32 methylation occurred in only 1 of 80 endometrial cancers, including 20 MSI-H, 8 MSI-L and 52 MSS tumors. Hypermethylation of hMLH1 was noted in 16 (20%) of 80 endometrial tumors. We conclude that although RAB32 methylation is rare in endometrial cancers, it is strongly associated with hMLH1 hypermethylation and MSI in gastric adenocarcinomas. Given its similar involvement in colon cancer, RAB32 inactivation may represent a component of the oncogenic pathway of microsatellite-unstable gastrointestinal adenocarcinomas.
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PMID:RAB32 hypermethylation and microsatellite instability in gastric and endometrial adenocarcinomas. 1655 77

There is an urgent need to identify and develop a new generation of therapeutic agents and systemic therapies targeting the estradiol (E2)/estrogen receptor (ER) signaling in breast cancer. In this regard, new information on the mechanisms of E2/ER function and/or cross talk with other prosurvival cascades should provide the basis for the development of other ideal anti-E2 therapies with the intent to enhance clinical efficacy, reduce side effects or both. Our very recent assessment of the mechanisms by which cancer-associated increased lipogenesis and its inhibition alters the E2/ER signaling discovered that fatty acid synthase (FASN), the enzyme catalyzing the terminal steps in the de novo biosynthesis of long-chain fatty acids, differentially modulates the state of sensitivity of breast and endometrial cancer cells to E2-stimulated ER transcriptional activation and E2-dependent cell growth and survival: 1) pharmacological inhibition of FASN activity induced a dramatic augmentation of E2-stimulated ER-driven gene transcription, whereas interference (RNAi)-mediated silencing of FAS gene expression drastically lowered E2 requirements for optimal activation of ER transcriptional activation in breast cancer cells; conversely, pharmacological and RNAi-induced inhibition of FASN worked as an antagonist of E2- and tamoxifen-dependent ER transcriptional activity in endometrial adenocarcinoma cells; 2) pharmacological and RNAi-induced inhibition of FASN synergistically enhanced E2-mediated down-regulation of ER protein and mRNA expression in breast cancer cells, whereas specific FASN blockade resulted in a marked down-regulation of E2-stimulated ER expression in endometrial cancer cells; and 3) FASN inhibition decreased cell proliferation and cell viability by promoting apoptosis in hormone-dependent breast and endometrial cancer cells. In this review we propose that, through a complex mechanism involving the regulation of MAPK/ER cross talk as well as critical E2-related proteins including the Her-2/neu (erbB-2) oncogene and the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(Kip1), a previously unrevealed connection exists between FASN and the genomic and nongenomic ER activities in breast and endometrial cancer cells. From a clinical perspective, we suggest that if chemically stable FASN inhibitors or cell-selective systems able to deliver RNAi targeting FASN gene demonstrate systemic anticancer effects of FASN inhibition in vivo, additional preclinical studies to characterize their anti-breast cancer actions should be of great interest as the specific blockade of FASN activity may also provide a protective means against endometrial carcinoma associated with tamoxifen-based breast cancer therapy.
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PMID:Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators? 1680 39

The phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway and the mitogen activated protein kinase (MAPK) pathway are important in the development and proliferation of various human cancers. It has been found recently that ursolic acid treatment affects growth and apoptosis in cancer cells. We sought to determine whether prominent signaling pathways, including the PI3K-Akt pathway and the MAPK (JNK, P38, and P44/42) pathway mediate these effects. Endometrial cancer cells often have high levels of phosphorylated Akt seen in conjunction with a PTEN mutation or deletion. Elevation in Akt protects the cancer cell from apoptosis. Ursolic acid treatment moderately decreased PI3K levels in SNG-II cells. Treatment also decreased phospho-Akt and phospho-P44/42 in a dose- and time-dependent fashion, dramatically in SNG-II cells and moderately in HEC108 cells. This effect was most pronounced following treatment with 50 mum ursolic acid for 72 h. Our study found inhibition of both the PI3K-Akt pathway and the MAPK pathway in two endometrial cancer cell lines, SNG-II and the poorly differentiated HEC108 cell line.
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PMID:Regulation of the phosphatidylinositol 3-kinase-Akt and the mitogen-activated protein kinase pathways by ursolic acid in human endometrial cancer cells. 1721 63

Estradiol-17beta (E(2)) causes cell proliferation in the uterine epithelium of mice and humans by signaling through its transcription factor receptor alpha (ERalpha). In this work we show that this signaling is mediated by the insulin-like growth factor 1 receptor (IGF1R) expressed in the epithelium, whose activation leads to the stimulation of the phosphoinositide 3-kinase/protein kinase B pathway leading to cyclin D1 nuclear accumulation and engagement with the canonical cell cycle machinery. This cyclin D1 nuclear accumulation results from the inhibition of glycogen synthase kinase 3beta (GSK3beta) activity caused by an inhibitory phosphorylation by protein kinase B. Once the IGF1 pathway is activated, inhibition of ER signaling demonstrates that it is independent of ER. Inhibition of GSK3beta in the absence of E(2) is sufficient to induce uterine epithelial cell proliferation, and GSK3beta is epistatic to IGF1 signaling, indicating a linear pathway from E(2) to cyclin D1. Exposure to E(2) is the major risk factor for endometrial cancer, suggesting that downstream activation of this IGF1-mediated pathway by mutation could be causal in the progression to ER-independent tumors.
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PMID:Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling. 1789 82

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising antineoplastic agent because of its ability to selectively kill tumoral cells. However, some cancer cells are resistant to TRAIL-induced apoptosis. We have previously demonstrated that in endometrial carcinoma cells such resistance is caused by elevated FLICE-inhibitory protein (FLIP) levels. The present study focuses on the mechanisms by which FLIP could be modulated to sensitize endometrial carcinoma cells to TRAIL-induced apoptosis. We find that inhibition of casein kinase (CK2) sensitizes endometrial carcinoma cells to TRAIL- and Fas-induced apoptosis. CK2 inhibition correlates with a reduction of FLIP protein, suggesting that CK2 regulates resistance to TRAIL and Fas by controlling FLIP levels. FLIP downregulation correlates with a reduction of mRNA and is prevented by addition of the MG-132, suggesting that CK2 inhibition results in a proteasome-mediated degradation of FLIP. Consistently, forced expression of FLIP restores resistance to TRAIL and Fas. Moreover, knockdown of either FADD or caspase-8 abrogates apoptosis triggered by inhibition of CK2, indicating that CK2 sensitization requires formation of functional DISC. Finally, because of the possible role of both TRAIL and CK2 in cancer therapy, we demonstrate that CK2 inhibition sensitizes primary endometrial carcinoma explants to TRAIL apoptosis. In conclusion, we demonstrate that CK2 regulates endometrial carcinoma cell sensitivity to TRAIL and Fas by regulating FLIP levels.
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PMID:CK2 controls TRAIL and Fas sensitivity by regulating FLIP levels in endometrial carcinoma cells. 1798 83

Prolonged exposure to unopposed estrogen in the absence of progesterone gives rise to endometrial hyperplasia and carcinoma. Post-ovulatory progesterone is necessary for the proper growth and differentiation of endometrial epithelial cells (EECs). Progesterone exposure induces the endometrial production of numerous bioactive substances, one of which is the glycoprotein, glycodelin (Gd). We investigated the role of Gd in cell cycle progression and cell growth to better understand how Gd affects EEC behavior and endometrial cancer pathogenesis. Ishikawa cells, a well-differentiated human endometrial epithelial cancer cell line, were transfected with expression plasmids encoding enhanced green fluorescent protein (EGFP) or EGFP-fused Gd (EGFP-Gd). They were then subjected to a cell proliferation assay, flow cytometry cell cycle analysis and RT-PCR analysis of cyclin-dependent kinase inhibitors (CDKIs) including p21, p27 and p16. Overexpression of EGFP-Gd resulted in a reduction of cell proliferation activity, an accumulation of G1-phase cells and up-regulation of p21, p27 and p16 mRNAs. Furthermore, progesterone-induced inhibition of Ishikawa cell growth was partially attenuated by Gd knockdown using siRNA. These results indicate that Gd causes inhibition of G1/S progression together with up-regulation of CDKIs thereby reducing cell growth. Thus, progesterone-induced expression of Gd may, at least in part, contribute to the suppression of endometrial epithelial growth observed during the secretory phase.
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PMID:Glycodelin blocks progression to S phase and inhibits cell growth: a possible progesterone-induced regulator for endometrial epithelial cell growth. 1817 6

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