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)

Recent discoveries on endocrine, paracrine and autocrine involvement of insulin-like growth factor-1 (IGF-1) in the proliferation of many tissues raised the attention of its role in reproduction and in the growth of various cancers as well as of benign proliferations. The intention of this article is to focus on IGF-1 in the field of gynaecology. Perimenopausal women who exhibit high IGF-1 and low IGF binding protein (IGFBP) levels, like IGFBG-3, have an increased risk of developing breast cancer. A higher risk for cervical, ovarian and endometrial cancer is related to high IGF-1 levels in post- and premenopausal women. It has been shown that myomas, by far the most common benign uterine tumor in women, grow in the presence of IGF-1, in vitro as well as in vivo. Studies show that IGF-1 is involved in the differentiation of various reproductive tissues, like endometrium and ovarian tissues. Patients suffering from polycystic ovary syndrome (PCO) frequently show insulin resistance accompanied by an increase of IGF-1 in plasma. Plasma IGF-1 levels are higher in cases of severe endometriosis, however, in endometriosis and in PCO IGF levels locally in the endometrium are reduced, what might explain infertility. Recently, it was shown that IGF facilitates the implantation of the human embryo in the endometrium during IVF. Implantation is a paradox where different immune systems have to collaborate to make implantation and survival of the pregnancy possible. IGF seems to be the starter molecule so that the two epithelia can fuse. A disturbance can result in complications during pregnancy i.e. spontaneous miscarriage, preeclampsia as well as defects of the embryo. Therefore, IGF is a useful marker in successful pregnancy as well. A better mechanistic understanding of IGF-1 action on the cellular level not only provides more elegant mechanistic explanations for the scientist, but the practitioner might find it interesting to utilize its diagnostic potential as a marker for various diseases. The relation between systemic IGF levels and local tissue IGF-1 levels has not yet been determined for all conditions.
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PMID:IGF-1 in gynaecology and obstetrics: update 2002. 1195 96

Polycystic ovary syndrome [PCOS] is the most common endocrinopathy of women in reproductive age. An association between PCOS and type-1 endometrial cancer has often been reported in the literature. The prolonged anovulation with consequent continued secretion of estrogen unopposed by progesterone may enhance the development and growth of this malignancy, particularly in young women. Hypersecretion of luteinizing hormone [LH], chronic hyperinsulinemia and increased serum insulin-like growth factor [IGF]-I levels may represent risk factors for endometrial cancer. However, data available in the literature do not allow a meta-analysis to be carried out to calculate an estimate of the relative risk of endometrial cancer in women with PCOS. Anecdotal cases of low-grade endometrial stromal sarcoma and carcinosarcoma have been reported in association with prolonged unopposed estrogen stimulation, and in particular with PCOS. A few studies have addressed the possibility of an association between PCOS and epithelial ovarian cancer risk, and the results are conflicting but generally reassuring, and similarly the few available data appear to exclude a strong association between PCOS and breast cancer.
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PMID:Polycystic ovary syndrome and gynecological cancers: is there a link? 1601 62

A novel in vivo model of tamoxifen-stimulated endometrial cancer was developed and the role of HER-2/neu investigated by using trastuzumab. Tamoxifen-stimulated tumors (ECC-1TAM) were growth stimulated by 17beta-estradiol (E2), tamoxifen, or raloxifene. Trastuzumab inhibited growth of E2-stimulated ECC-1E2 tumors by 50% and tamoxifen-stimulated ECC-1TAM tumors by 100%. ECC-1 tumors expressed functional estrogen receptor alpha (ER alpha) as measured by induction of pS2 and c-myc mRNAs. E2 induced pS2 and c-myc mRNAs up to 40-fold in ECC-1E2 and ECC-1TAM. Tamoxifen induced pS2 and c-myc mRNAs up to 5-fold in ECC-1E2 tumors and up to 10-fold in ECC-TAM tumors. Trastuzumab blocked E2-induced pS2 mRNA (P < 0.01) in ECC-1E2 by 50% and tamoxifen-induced c-myc mRNA (P < 0.1) in ECC-1TAM tumors by 70%. Trastuzumab decreased phosphorylated and total HER-2/neu protein in ECC-1E2 and ECC-1TAM tumors. However, only phospho-ERK-1/2 and not phospho-Akt protein was decreased by trastuzumab in tamoxifen-treated ECC-1TAM tumors. The insulin-like growth factor (IGF-I) signaling pathway also activates extracellular signal-related kinase (ERK)-1/2 and could block the efficacy of trastuzumab in ECC-1E2 tumors. The results showed that IGF-I, IGF-IR mRNAs, and phospho-insulin receptor substrate-1 (IRS-1) protein were decreased in ECC-1TAM compared with ECC-1E2 tumors. The results show that trastuzumab is an effective therapy for both E2-stimulated and tamoxifen-stimulated endometrial cancer. The data suggest estrogenic activities of E2 and tamoxifen at ER alpha-regulated pS2 and c-myc genes are in part mediated by HER-2/neu. However, trastuzumab is a better growth inhibitor of ECC-1TAM tumors where there is diminished IGF-I signaling allowing for complete blockade of the downstream phospho-ERK-1/2 signal.
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PMID:Trastuzumab therapy for tamoxifen-stimulated endometrial cancer. 1616 31

We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition, to examine the associations between prediagnostic serum concentrations of C-peptide, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-2, and endometrial cancer risk. Among pre- and post-menopausal women, who were not currently using exogenous hormones, 286 women developed incident endometrial cancer during an average 5.1 years follow-up. Using risk set sampling, 555 matched control subjects were selected. In conditional logistic regression models adjusted for matching factors only, endometrial cancer risk increased with increasing serum levels of C-peptide (relative risks (RR) for the top vs. bottom quartile = 2.13 [95% confidence interval (CI) 1.33-3.41], p(trend) = 0.001, and decreasing serum levels of IGFBP-2 (RR for the top vs. bottom quartile = 0.56 [95% CI 0.35-0.90], p(trend) = 0.03, but was not significantly associated with IGFBP-1 levels (RR for the top vs. bottom quartile = 0.76 [95% CI 0.47-1.21], p(trend) = 0.25). In BMI-adjusted models, only the C-peptide association remained marginally statistically significant (RR for the top vs. bottom quartile = 1.56 [95% CI 0.94-2.57], p(trend) = 0.05 for C-peptide; 0.84 [95% CI 0.50-1.40], p(trend) = 0.74 for IGFBP-2; and 1.08 [95% CI 0.65-1.78], p(trend) = 0.86 for IGFBP-1 levels). These associations were stronger among nonfasting women (< or =< or =6 hr since last meal; 63% of subjects) but were not evident among fasting women, although the interactions were not statistically significant. The C-peptide-risk association was substantially attenuated after adjustment for free estradiol in postmenopausal women (RR for the top vs. bottom quartile = 1.28 [95% CI 0.67-2.45], p(trend) = 0.42. Our results provide modest support to the hypothesis that hyperinsulinaemia is a risk factor for endometrial cancer.
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PMID:Serum levels of C-peptide, IGFBP-1 and IGFBP-2 and endometrial cancer risk; results from the European prospective investigation into cancer and nutrition. 1728 78

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) can induce estrogenic action or inhibit estrogen-induced effects in various tissues because of aryl hydrocarbon receptor (AhR)-estrogen receptor (ER) cross-talk. In order to identify the biomarkers of TCDD endocrine disruption, we screened estrogen-responsive genes modified by TCDD exposure using specific cDNA microarrays spotted with estrogen-responsive genes. MCF-7 human breast carcinoma cells and RL95-2 human endometrial carcinoma cells were exposed to TCDD, and an analysis of their gene expression revealed 32 genes exhibiting a significant change. The mRNA expression levels of 27 genes were subsequently verified using real-time RT-PCR. Among these genes, bioinformatic analyses indicated that insulin-like growth factor-binding protein 5 (IGFBP5) gene expression might be influenced by estrogen status. In our animal experiments, IGFBP5 was also shown to be responsive to TCDD exposure in mouse fetuses in utero. These results suggest that TCDD affects the expression levels of a series of estrogen-responsive genes, and follow-up fetal studies in mice indicated that IGFBP5 is useful as a biomarker of TCDD activity.
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PMID:Estrogen-responsive genes newly found to be modified by TCDD exposure in human cell lines and mouse systems. 1755 68

The insulin-like growth factor (IGF) is a complex system of peptide hormones (insulin-like growth factors of type 1 and 2, IGF-1 and IGF-2), cell surface receptors (insulin receptor, IR; insulin-like growth factor receptors of type 1 and 2, IGF-R1, IGF-R2) and circulating binding proteins (insulinlike growth factor binding proteins, IGF-BP 1-6). IGF-1 and -2 are mitogens that play a role in regulating cell proliferation, differentiation and apoptosis. Their effects are mediated through the IGF-R1 which initiates signaling cascades that result in regulation of a number of biological responses. IGF-R2, together with IGF-BPs is involved in binding, internalization and degradation of IGF-2. IGF proteins regulate cell proliferation in an interconnected action via autocrine, paracrine and endocrine regulatory mechanisms. Consequently, any perturbation in each level of the IGF signaling proteins has been shown to be implicated in development and progression of numerous cancer types. The most important single components in this processes are IGF ligands as well as IGF-R1 - when disturbed they act as oncogenes. It has been shown that: (i) high serum concentrations of IGF-1 and IGF-2 are associated with an increased risk of breast, prostate, colorectal and lung cancers; and (ii) IGF-R1 is commonly disturbed in many tumours (like gastric, lung, endometrial cancer) leading to a phenotype of anchorage-independent tumour growth. In contrast, IGF-R2 is considered to act as a tumour suppressor gene; it protects the cells from neoplastic impulses. Consistent with the IGFs autocrine/paracrine regulation of tumour growth, cancer treatment strategies interfering with IGF-R1 signaling have been developed, that may be useful in future diagnostic and therapeutic strategies.
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PMID:Biological & physiological aspects of action of insulin-like growth factor peptide family. 1759 37

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein highly expressed in fetal tissue and malignant tumors but rarely found in adult benign tissues. The aim of this study is to determine the expression of IMP3 in benign endometrium, endometrial cancer, and its precursor lesions, trying to see whether IMP3 has any diagnostic usage. Two hundred ninety-eight endometrial samples were examined for IMP3 expression by immunohistochemistry. These included benign endometrium (n=68), atypical hyperplasia or endometrial intraepithelial neoplasia (n=35), endometrial glandular dysplasia (n=21), endometrial intraepithelial carcinoma (n=18), endometrioid carcinoma (n=70), mucinous carcinoma (n=8), serous carcinoma (n=51), clear cell carcinoma (n=12), and other malignancies (n=15). Maturational patterns in the 68 benign endometrial samples included atrophic (n=12), proliferative (n=18), secretory (n=14), menstrual (n=8), and gestational (n=16). Most of the carcinomas were histologically pure; where mixed, the second component constituted <10% of the total tumor volume. The extent and intensity of IMP3 expression was semiquantitatively determined and scored for all samples. A renal cell carcinoma with known IMP3 expression was used as positive control for each immunohistochemistry run. Among the malignant cases, IMP3 expression was predominantly found in endometrial serous carcinoma and its putative precursor lesions, with 3 (14%) of 21 endometrial glandular dysplasia, 16 (89%) of 18 serous endometrial intraepithelial carcinoma, and 48 (94%) of 51 serous carcinomas (P<0.001). In contrast, the frequency of IMP3 expression was significantly lesser in nonserous malignancies with 0 (0%) of 35, 5 (7%) of 70, 0 (0%) of 8, 3 (25%) of 12, and 5 (33%) of 15 positive expression rates in atypical hyperplasia or endometrial intraepithelial neoplasia, endometrioid, mucinous, clear cell carcinomas, and other malignancies, respectively. The IMP3 staining was universally cytoplasmic, with diffuse staining of strong intensity in serous carcinomas, whereas staining was typically patchy and of moderate or weak intensity in nonserous malignancies. Among the benign endometrial samples, decidualized endometrial stroma showed 100% positivity for IMP3. The remaining samples were negative, with the exception of a few weakly proliferative glands in 3 (5%) of 68 cases that showed focal weak immunoreactivity of IMP3. The trophoblasts in the first trimester chorionic villi were also diffusely positive, which was consistent with previously reported findings. We conclude that expression of IMP3, a newly identified cytoplasmic marker, is closely associated with type II endometrial cancer. It seems that IMP3 expression is associated with an aggressive histologic phenotype among endometrial neoplastic lesions. Strong and diffuse IMP3 expression is highly sensitive for endometrial serous and clear cell carcinomas including their putative precursor lesions. Therefore, IMP3 may be a useful diagnostic marker in the assessment of endometrial cancers and their precursor lesions, particularly when the amount of available tissue material is limited and a concern of type II cancer arises. High frequency of IMP3 expression is present in decidualized endometrial stroma of gestational endometrium and chorionic villi in early pregnancy. Although the significance of the latter finding remains unclear, the differential diagnosis between decidual changes and endometrial serous carcinoma is rarely problematic.
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PMID:The oncofetal protein IMP3: a novel biomarker for endometrial serous carcinoma. 1822 34

Tamoxifen is an important selective estrogen receptor (ER) modulator for treatment of steroid hormone positive breast cancer. In addition to the beneficial effect, tamoxifen is one risk factor for endometrial carcinoma (EnCa) development. We hypothesized that, (1) dysregulation of gene expression and protein phosphorylation of the insulin-like growth factor (IGF) and steroid hormone receptor-signaling occur early in benign endometrial tissues and (2) signaling differences would be detected between patients with or without tamoxifen treatment. Seventy-eight tissues, including 2 benign cohorts from patients treated with (n = 24) or without tamoxifen (n = 28) (hyperproliferative endometrium, hyperplasia, polyps), EnCa (n = 12) with endometrium controls (n = 14) were analyzed for expression of 15 genes from the IGF and steroid hormone receptor-signaling, including the target genes Syncytin-1, PAX2 and c-myc. Total and phosphorylated protein expression were examined for ERalpha, PTEN, AKT, mTOR and Syncytin-1. Compared to controls similar significant deregulation of IGF and steroid hormone receptor-signaling, Syncytin-1 and PAX2 occurred in both benign cohorts, irrelevant of tamoxifen treatment. Comparing both benign cohorts with and without tamoxifen significant expression differences were noted. Increased total protein and phosphorylation of pERalpha-Ser118, pPTEN-Thr380, pAKT-Thr308, pAKT-Ser473, pmTOR-Ser2448 and Syncytin-1 were noted in early benign tissue stages associating with tamoxifen, especially polyps. Functional kinetic studies following tamoxifen treatment of the PTEN mutated RL95-2 EnCa cell line, demonstrated a doubling of phosphorylation of pERalpha-Ser118 and a 4.2-fold induction of pAKT-Thr308 along with Syncytin-1 induction. This study supports that dysregulated IGF and steroid hormone receptor signaling is prominent in endometrial benign stages and these alterations could represent clinical indicators for the risk of EnCa and also help in development of new therapies.
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PMID:Early aberrant insulin-like growth factor signaling in the progression to endometrial carcinoma is augmented by tamoxifen. 1881 40

Insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF-IR) can assemble heteromerically as a hybrid insulin/IGF-I receptor (hybrid-R) in tissues that express both molecules. There is little information about hybrid-R in endometrial carcinoma, in which both IR and IGF-IR are frequently overexpressed. We used immunoprecipitation to detect hybrid-R expression in two endometrial carcinoma cell lines: HEC-1a, which has low estrogen receptor (ER) expression, and Ishikawa, which is positive for ER expression. To explore the role of hybrid-R in endometrial carcinoma cells, we examined phosphorylation of extracellular signal-regulated kinase (ERK1/2), which is a key molecule in the mitogen-activated protein kinase (MAPK) pathway. The effect of inhibiting IGF-I, IGF-II, and insulin on cell cycle progression and apoptosis was assessed by flow cytometry. Both cell lines expressed hybrid-R, and HEC-1a cells had higher expression levels than did Ishikawa cells. IGF-I induced ERK1/2 phosphorylation in HEC-1a cells mainly through hybrid-R; in Ishikawa cells, this effect was mediated only in part by hybrid-R. Insulin stimulated ERK1/2 phosphorylation partly through hybrid-R in HEC-1a cells, but not in Ishikawa cells. Both IGFs and insulin increased cellular DNA content in the S phase of the cell cycle in HEC-1a through hybrid-R. In contrast, in Ishikawa cells, only insulin enhanced DNA content in S phase through hybrid-R. Both IGFs and insulin significantly decreased apoptosis in HEC-1a cells through hybrid-R, and a similar but moderate effect was observed in Ishikawa cells. Hybrid-R, which is present in endometrial carcinoma cells, may have an important role in mediating IGF- and insulin-induced cell growth and in preventing apoptosis.
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PMID:The expression and role of hybrid insulin/insulin-like growth factor receptor type 1 in endometrial carcinoma cells. 2062 May 97

The type-1 insulin-like growth factor receptor (IGF-1R) is one member of tyrosine protein kinase receptor family. It is a causal factor for tumor initiation, development and frequently overactivated in a variety of human malignancies, including endometrial carcinoma. To investigate its possibility as a therapeutic target for endometrial carcinoma, we adopted RNA interference technology to down-regulate IGF-1R expression in endometrial carcinoma and analyzed its apoptosis inductive effect and tumorigenicity in vivo. Results showed that RNAi mediated down-regulation of IGF-1R expression in endometrial carcinoma significantly induced apoptosis, reduced downstream protein phosphorylation and decreased tumorigenicity in vivo accompanied with lower proliferation index in tumor tissue, Which implied the therapeutic potential of RNAi in the treatment of endometrial carcinoma by targeting IGF-1R and IGF-1R may be a potential therapeutic target for human endometrial carcinoma.
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PMID:Inhibitory effect of siRNA targeting IGF-1R on endometrial carcinoma. 2114 98

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