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

Endometrial carcinoma is the most common malignancy of the female genital tract in industrialized countries. Metastasis is the major cause of endometrial cancer deaths. Therefore, there is a vital need for clinically relevant in vivo models allowing the elucidation of the molecular and cellular mechanisms underlying metastatic behavior. In this study, we describe an innovative experimental orthotopic model of human endometrial carcinoma. Implantation in the bifurcation of the uterine horns resulted in tumors integrated into the myometrial compartment, which can be used and further exploited for the study of in vivo angiogenesis, myometrial invasion, and the metastatic capacity of endometrial cancer cells. This orthotopic model also represents a suitable tool to analyze how tumorigenesis and distant metastasis of endometrial cancer might be influenced by gene alteration, by modulating its expression in the original cancer cell line. One of the candidate genes implicated in endometrial cancer is the transcription factor RUNX1. The over-expression of RUNX1 in the endometrial cancer cell line HEC1A and the transplantation of these cells to the uterus of nude mice were associated specifically with distant metastasis in the lung. RUNX1 plays a role in the establishment of metastases in endometrial cancer. Translated to the clinics, these models would be equivalent to an advanced undifferentiated carcinoma with node affectation (stage IIIC) and distant metastasis (stage IVB). These patients would be candidates for adjuvant therapy, not efficient until today, and therefore, our models are actually suitable for the design and evaluation of experimental therapies.
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PMID:An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis. 1938 51

Uterine carcinosarcomas (UCSs) are considered to represent true examples of the epithelial-mesenchymal transition. Akt plays a key role in the induction of epithelial-mesenchymal transition, but little is known about its involvement in tumorigenesis. Here we examined the functional roles of the Akt/beta-catenin pathway in UCSs. In clinical samples, phospho-Akt (pAkt) expression was found to be significantly increased in mesenchymal compared with epithelial components, exhibiting both positive and negative correlations with nuclear beta-catenin and E-cadherin, respectively. Expression levels of the transcription factor Slug were also significantly up-regulated in the mesenchymal components and strongly correlated with both pAkt and nuclear beta-catenin. In endometrial cancer cell lines, active Akt induced the stabilization of nuclear beta-catenin through the phosphorylation of GSK-3beta, and this, in turn, led to the transactivation of Slug, which was mediated by nuclear beta-catenin. Moreover, Slug overexpression itself caused repression of E-cadherin, with subtle changes in cell morphology. In addition, knockdown of the retinoblastoma gene product (Rb) up-regulated pAkt and repressed E-cadherin, consistent with the in vivo finding of significantly decreased Rb expression in mesenchymal components. These findings suggest that changes in the Akt/beta-catenin pathway, as well as alterations in Rb expression, may be essential for both the establishment and maintenance of phenotypic characteristics of UCSs, playing key roles in the regulation of E-cadherin through the transactivation of the Slug gene.
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PMID:Requirement of the Akt/beta-catenin pathway for uterine carcinosarcoma genesis, modulating E-cadherin expression through the transactivation of slug. 1938 26

DKK1 is a negative regulator in the Wnt signal transduction pathway. It can inhibit the pathway's activation. Previous studies in some malignant tumors revealed the possibility that DKK1 is involved in tumorigenesis inducing abnormalities of the Wnt signal pathway. In this study, we showed that in benign and malignant endometrium, DKK1 exhibited novel expression profiles and invasiveness-related biology function: DKK1 was expressed in both glandular epithelium and matrix of two kinds of endometrium tissues and mostly distributed in the cytoplasm and epicytes of endometrial carcinoma (EC) Ishikawa cell line. DKK1 expression level in EC was significantly lower than that in benign endometrium. The expression correlated well with histology and clinical stage of EC. Exogenous DKK1 suppressed invasiveness of EC cells. Taken together, DKK1 is involved in genesis and early phase of EC by suppressing the invasiveness via the Wnt signal pathway. It shows promise as a biomarker for screening the progression of EC.
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PMID:Novel expression profiles and invasiveness-related biology function of DKK1 in endometrial carcinoma. 1942 19

c-Jun N-terminal kinases (JNKs) are important regulators of cell proliferation and apoptosis that have been implicated in tumorigenesis. We investigated the role of JNKs in apoptotic responses in Ishikawa and HEC-50 cells, models of type I and type II endometrial cancer, respectively. Etoposide treatment or UV irradiation resulted in sustained activation of JNK, correlating with the induction of apoptosis. Inhibition of JNK, or MAP kinase kinase 4 (MKK4), selectively suppressed apoptotic responses in both Ishikawa and HEC-50 cells. Knockdown of protein kinase C delta (PKCdelta) also attenuated apoptosis in endometrial cancer cells and inhibited the sustained, UV-mediated JNK activation in HEC-50, but not Ishikawa cells. Etoposide-induced JNK phosphorylation was unaffected by PKCdelta knockdown, implying that JNK can regulate apoptosis by PKCdelta-dependent and independent pathways, according to stimulus and cell type. Thus, expression and activity of JNK and PKCdelta in endometrial cancer cells modulate apoptosis and sensitivity to chemotherapeutic agents and may function as tumor suppressors in the endometrium.
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PMID:c-Jun N-terminal kinase regulates apoptosis in endometrial cancer cells. 1942

There is increasing evidence that prolactin (PRL), a hormone/cytokine, plays a role in breast, prostate, and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported, indicating a potential role for PRL in endometrial and ovarian carcinogenesis. In this study, we show that serum PRL levels are significantly elevated in women with a strong family history of ovarian cancer. We show dramatically increased expression of PRL receptor in ovarian and endometrial tumors as well as in endometrial hyperplasia, signifying the importance of PRL signaling in malignant and premalignant conditions. PRL mRNA was expressed in ovarian and endometrial tumors, indicating the presence of an autocrine loop. PRL potently induced proliferation in several ovarian and endometrial cancer cell lines. Binding of PRL to its receptor was followed by rapid phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, mitogen-activated protein kinase/ERK kinase 1, signal transducer and activator of transcription 3, CREB, ATF-2, and p53 and activation of 37 transcription factors in ovarian and endometrial carcinoma cells. PRL also activated Ras oncogene in these cells. When human immortalized normal ovarian epithelial cells were chronically exposed to PRL, a malignant transformation occurred manifested by the acquired ability of transformed cells to form clones, grow in soft agar, and form tumors in severe combined immunodeficient-beige mice. Transformation efficiency was diminished by a Ras inhibitor, providing proof that PRL-induced transformation uses the Ras pathway. In summary, we present findings that indicate an important role for PRL in ovarian and endometrial tumorigenesis. PRL may represent a risk factor for ovarian and endometrial cancers.
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PMID:Biological significance of prolactin in gynecologic cancers. 1949 Dec 63

A single tumor may contain cells with different somatic mutations. By characterizing this genetic heterogeneity within tumors, advances have been made in the prognosis, treatment and understanding of tumorigenesis. In contrast, the extent of epigenetic intra-tumor heterogeneity and how it influences tumor biology is under-explored. We have characterized epigenetic heterogeneity within individual tumors using next-generation sequencing. We used deep single molecule bisulfite sequencing and sample-specific DNA barcodes to determine the spectrum of MLH1 promoter methylation across an average of 1000 molecules in each of 33 individual samples in parallel, including endometrial cancer, matched blood and normal endometrium. This first glimpse, deep into each tumor, revealed unexpectedly heterogeneous patterns of methylation at the MLH1 promoter within a subset of endometrial tumors. This high-resolution analysis allowed us to measure the clonality of methylation in individual tumors and gain insight into the accumulation of aberrant promoter methylation on both alleles during tumorigenesis.
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PMID:Intra-tumor heterogeneity of MLH1 promoter methylation revealed by deep single molecule bisulfite sequencing. 1949 83

Endometrial cancer is the most common invasive gynecologic malignancy, yet molecular mechanisms and signaling pathways underlying its etiology and pathophysiology remain poorly characterized. We sought to define a functional role for the protein kinase C (PKC) isoform, PKCalpha, in an established cell model of endometrial adenocarcinoma. Ishikawa cells depleted of PKCalpha protein grew slower, formed fewer colonies in anchorage-independent growth assays and exhibited impaired xenograft tumor formation in nude mice. Consistent with impaired growth, PKCalpha knockdown increased levels of the cyclin-dependent kinase (CDK) inhibitors p21(Cip1/WAF1) (p21) and p27(Kip1) (p27). Despite the absence of functional phosphatase and tensin homolog (PTEN) protein in Ishikawa cells, PKCalpha knockdown reduced Akt phosphorylation at serine 473 and concomitantly inhibited phosphorylation of the Akt target, glycogen synthase kinase-3beta (GSK-3beta). PKCalpha knockdown also resulted in decreased basal ERK phosphorylation and attenuated ERK activation following EGF stimulation. p21 and p27 expression was not increased by treatment of Ishikawa cells with ERK and Akt inhibitors, suggesting that PKCalpha regulates CDK expression independently of Akt and ERK. Immunohistochemical analysis of Grade 1 endometrioid adenocarcinoma revealed aberrant PKCalpha expression, with foci of elevated PKCalpha staining, not observed in normal endometrium. These studies demonstrate a critical role for PKCalpha signaling in endometrial tumorigenesis by regulating expression of CDK inhibitors p21 and p27 and activation of Akt and ERK-dependent proliferative pathways. Thus, targeting PKCalpha may provide novel therapeutic options in endometrial tumors.
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PMID:Protein kinase C alpha-dependent signaling mediates endometrial cancer cell growth and tumorigenesis. 1967 62

Cytochrome P450 1B1 (CYP1B1) catalyzes estrogen hydroxylation and activation of potential carcinogens. Here we explored the role of CYP1B1 in endometrial carcinogenesis. Immunohistochemical staining of endometrial carcinomas showed that CYP1B1 is up-regulated in endometrial cancers. To understand the functional significance of CYP1B1 up-regulation in endometrial cancers with regard to tumorigenesis, we used small interfering RNA-mediated approach to knockdown CYP1B1 in endometrial carcinoma cell line followed by functional assays. Further, to understand the molecular basis of the role of CYP1B1 in endometrial carcinomas, we profiled the expression of key pathway-specific genes and identified several components of cell cycle, apoptosis, and cell adhesion pathways that are potentially regulated by CYP1B1. CYP1B1 depletion in endometrial carcinoma cells leads to decreased cellular proliferation and induces G(0)-G(1) cell cycle arrest. Significantly, CYP1B1 knockdown leads to down-regulated expression of cyclin E1, S-phase kinase-associated protein 2 (SKP2), minichromosome maintenance complex component 4 (MCM4), and RAD51 and up-regulation of p27(Kip1). Also, we identified cyclin E-binding protein (CEBP1) as a novel CYP1B1 target. Attenuation of CYP1B1 expression in endometrial carcinoma cells induces apoptosis and increases expression of IFN-beta (IFNbeta), granzyme A (GRZA), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Importantly, CYP1B1 depletion decreased the invasive potential of the endometrial cancer cells and expression of melanoma cell adhesion molecule (MCAM). In conclusion, our data suggest that CYP1B1 up-regulation plays a crucial role in endometrial carcinogenesis by targeting multiple pathways. We speculate that CYP1B1 inhibition in endometrial carcinomas could be a useful therapeutic approach as it regulates several potential anticancer targets like cyclin E1, Skp2, and TRAIL.
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PMID:Functional significance of cytochrome P450 1B1 in endometrial carcinogenesis. 1969 Jan 33

Heat shock protein 70 (HSP70), an intracellular chaperone "stress protein," has been identified in the extracellular milieu, where it may exert regulatory effects upon monocytes. HSPs are overexpressed in many cancers and implicated in tumorigenesis. Few studies have examined the relationship between psychosocial factors and HSP levels, particularly in cancer. The purpose of the present study was to examine the relationship between negative psychosocial states (life events stress and negative mood states) and serum concentration of HSP70 antibodies among women with endometrial cancer, the fourth most common cancer among women in the United States. Thirty-six women scheduled to undergo surgery for suspected endometrial adenocarcinoma underwent a psychosocial assessment and peripheral venous blood draw. Life events stress was assessed using an abbreviated version of the Life Experiences Survey; negative mood states were assessed using abbreviated versions of the Structured Interview Guide for the Hamilton Anxiety and Depression Scales and the Profile of Mood States. HSP70 antibody levels were regressed sequentially on life events stress and negative mood variables while controlling for body mass index (BMI) and cancer stage. Results revealed that greater HSP70 antibody concentrations were associated with greater impact of recent negative life events (p=.04), anxious symptomatology (p=.007), depressive symptomatology (p=.03), and total mood disturbance (p=.001) after controlling for BMI and cancer stage. While based on a modest sample size, these preliminary results suggest that larger-scale research exploring the relationships among psychosocial factors and HSP70 in cancer patients may be warranted.
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PMID:Life stress, negative mood states, and antibodies to heat shock protein 70 in endometrial cancer. 1971 11

In the context of multiple neuroendocrine tumor syndromes, reproductive abnormalities may occur via a number of different mechanisms, such as hyperprolactinemia, increased GH/IGF-1 levels, hypogonadotropic hypogonadism, hypercortisolism, hyperandrogenism, hyperthyroidism, gonadotropin hypersecretion, as well as, tumorigenesis or functional disturbances in gonads or other reproductive organs. Precocious puberty and/or male feminization is a feature of McCune-Albright syndrome (MAS), neurofibromatosis type 1 (NF1), Carney complex (CNC), and Peutz-Jeghers syndrome (PJS), while sperm maturation and ovulation defects have been described in MAS and CNC. Although tumorigenesis of reproductive organs due to a multiple neuroendocrine tumor syndrome is very rare, certain lesions are characteristic and very unusual in the general population. Awareness leading to their recognition is important especially when other endocrine abnormalities coexist, as occasionally they may even be the first manifestation of a syndrome. Lesions such as certain types of ovarian cysts (MAS, CNC), pseudogynecomastia due to neurofibromas of the nipple-areola area (NF1), breast disease (CNC and Cowden disease (CD)), cysts and 'hypernephroid' tumors of the epididymis or bilateral papillary cystadenomas (mesosalpinx cysts) and endometrioid cystadenomas of the broad ligament (von Hippel-Lindau disease), testicular Sertoli calcifying tumors (CNC, PJS) monolateral or bilateral macroochidism and microlithiasis (MAS) may offer diagnostic clues. In addition, multiple neuroendocrine tumor syndromes may be complicated by reproductive malignancies including ovarian cancer in CNC, breast and endometrial cancer in CD, breast malignancies in NF1, and malignant sex-cord stromal tumors in PJS.
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PMID:Reproductive disturbances in multiple neuroendocrine tumor syndromes. 1973 12


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