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

Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway are common in endometrial carcinoma. Inactivation of the tumor suppressor gene PTEN leads to a constitutively active PI3K pathway, which plays a role in the early steps of endometrial tumorigenesis. Other alterations in the PI3K/AKT pathway are mutations in the PIK3CA gene, which encode the p110alpha catalytic subunit of PI3K. PIK3CA mutations cluster to the helical (exon 9) and the kinase (exon 20) domains of the gene. In endometrial carcinomas, PIK3CA mutations have been found to coexist frequently with PTEN mutations, but it is not clear whether they occur in cells with monoallelic or biallelic inactivation of PTEN. In the present study we have evaluated PIK3CA mutational status in a series of 33 endometrial carcinomas, previously screened for microsatellite instability and mutations in PTEN, K-RAS, and CTNNB-1. The tumors were also evaluated for loss of heterozygosity on 10q23 and hypermethylation of the promoter region of PTEN/psiPTEN to assess the monoallelic or biallelic inactivation status of PTEN. PIK3CA mutations were detected in 8 (24%) of the 33 cases. Seven mutations were located in exon 20 and 1 in exon 9. PTEN alterations were found in 19 cases (57%). Biallelic inactivation of PTEN was demonstrated in 11 tumors, whereas 8 tumors exhibited alteration in only 1 of the 2 alleles. PIK3CA mutations coexisted with monoallelic alterations of PTEN in 4 cases (2 mutations and 2 allelic imbalances), with biallelic PTEN inactivation in 1 case (mutation and promoter methylation), and 3 tumors showed PIK3CA mutations in association with wild-type PTEN. PIK3CA mutations did not correlate with microsatellite instability or mutations in CTNNB-1. However, PIK3CA and K-RAS mutations (8 cases) were mutually exclusive alterations. In summary, the results confirm that PIK3CA mutations are frequent in endometrial carcinoma and support the hypothesis that PIK3CA mutations may have an additive effect to PTEN monoallelic inactivation in endometrial carcinoma.
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PMID:PIK3CA gene mutations in endometrial carcinoma: correlation with PTEN and K-RAS alterations. 1694 21

Endometrial cancer is the third most common gynecologic malignancy and the ninth most common malignancy for females overall in Hong Kong. Approximately 80% or more of these cancers are endometrioid endometrial adenocarcinomas. The aim of this study was to reveal genes contributing to the development of endometrioid endometrial cancer, which may impact diagnosis, prognosis and treatment of the disease. Whole-genome gene expression analysis was completed for a set of 55 microdissected sporadic endometrioid endometrial adenocarcinomas and 29 microdissected normal endometrium specimens using the Affymetrix Human U133 Plus 2.0 oligonucleotide microarray. Selected genes of interest were validated by quantitative real-time-polymerase chain reaction (qRT-PCR). Pathway analysis was performed to reveal gene interactions involved in endometrial tumorigenesis. Unsupervised hierarchical clustering displayed a distinct separation between the endometrioid adenocarcinomas and normal endometrium samples. Supervised analysis identified 117 highly differentially regulated genes (>or=4.0-fold change), which distinguished the endometrial cancer specimens from normal endometrium. Twelve novel genes including DKK4, ZIC1, KIF1A, SAA2, LOC16378, ALPP2, CCL20, CXCL5, BST2, OLFM1, KLRC1 and MBC45780 were deregulated in the endometrial cancer, and further validated in an independent set of 56 cancer and 29 normal samples using qRT-PCR. In addition, 10 genes were differentially regulated in late-stage cancer, as compared to early-stage disease, and may be involved in tumor progression. Pathway analysis of the expression data from this tumor revealed an interconnected network consisting of 21 aberrantly regulated genes involved in angiogenesis, cell proliferation and chromosomal instability. The results of this study highlight the molecular features of endometrioid endometrial cancer and provide insight into the events underlying the development and progression of endometrioid endometrial cancer.
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PMID:Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling. 1704 62

Endometrial cancer is the most common invasive gynecologic malignancy but the molecular mechanisms underlying its onset and progression are poorly understood. Paradoxically, endometrial tumors exhibit increased apoptosis, correlating with disease progression and poor patient prognosis. Endometrial tumors also show altered activity and expression of protein kinase C (PKC) isoforms, implicated in the regulation of programmed cell death; however, PKC modulation of apoptosis in endometrial cancer cells has not been investigated. We detected nine out of ten PKC isoforms in Ishikawa endometrial cancer cell lines, and demonstrated expression of both PKCalpha and delta in human endometrial tumors. To determine the functional roles of PKCalpha and delta in apoptosis in endometrial cancer, Ishikawa cells were treated with selective PKC inhibitors or adenoviral constructs encoding wild-type or isoform-specific, dominant-negative mutants. Apoptosis was assessed by DNA fragmentation and caspase-mediated poly-(ADP-ribose)-polymerase cleavage. The inhibition of PKCdelta suppressed etoposide-induced apoptosis, while overexpression of PKCdelta enhanced it. In contrast, inhibition of PKCalpha elevated basal levels of apoptosis and potentiated etoposide-induced cell death. Etoposide treatment also selectively activated PKCdelta, but resulted in both cytosolic translocation and decreased activity of PKCalpha. A fraction of PKCdelta also underwent caspase-dependent cleavage, in response to etoposide. Our results suggest that changes in apoptosis and PKC expression in endometrial cancer are mechanistically linked, such that PKCdelta is required for DNA damage-induced apoptosis, while PKCalpha mediates a survival response. Thus, PKCalpha and delta expression and signaling may be important in endometrial tumorigenesis and could serve as potential prognostic indicators and/or novel targets for therapeutic intervention.
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PMID:Endometrial cancer cell survival and apoptosis is regulated by protein kinase C alpha and delta. 1715 69

The activation of signal transducer and activator of transcription 3 (Stat3) has been implicated in the oncogenesis of cancer and is regarded as a novel target for cancer therapy. Stat3 is classified as a proto-oncogene, because an activated form of Stat3 can mediate oncogenic transformation in cultured cells and tumour formation in nude mice. The constitutive activation of Stat3 has been frequently detected in various types of human cancers. However, the constitutive activation of Stat3 in endometrial and cervical cancers has not been studied. We examined tyrosine phosphorylation of Stat3 (activated form of Stat3) in multiple endometrial and cervical cancer tissues using tissue microarray slides as well as cancer cell lines to explore the possible activation of Stat3. Our results indicated that elevated phosphorylation of Stat3 was detected in cervical and endometrial cancer cell lines. Our results also showed that elevated levels of phosphorylation of Stat3 protein were detected in the endometrial and cervical cancer specimens. This is the first study to demonstrate that Stat3 is activated in human endometrial and cervical cancer tissues. Immunohistochemical staining showed that activated Stat3 is associated with increased expression of downstream antiapoptotic genes, Bcl-xL, survivin, and Mcl-1 in these tissues. Expression of a dominant-negative Stat3 mutant using adenovirus-mediated gene transfer inhibited cell growth and induced apoptosis in HeLa and SiHa cervical cancer cell lines expressing elevated levels of Stat3 phosphorylation. Further, a JAK/Stat3 small molecular inhibitor, JSI-124, induced apoptosis more selectively in HeLa and SiHa cancer cell lines than Ishikawa cell line without elevated levels of Stat3 phosphorylation. These results indicate that Stat3 is activated in human endometrial and cervical cancers and the inhibition of constitutive Stat3 signaling may be an effective target for cancer intervention in these two cancers.
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PMID:Stat3 activation in human endometrial and cervical cancers. 1731 Oct 11

PTEN is a tumor suppressor gene that is frequently mutated in type I endometrioid endometrial carcinomas (EECs), and is involved in the control of cell proliferation, differentiation, and apoptosis. In this study, we aimed to assess the relationship between PTEN expression and estrogen, progesterone receptors (PRs), other apoptosis-related proteins, such as bcl-2 and bax, and apoptotic index (AI) in EEC, its precursor lesion hyperplasia, and cyclical endometrium. We also evaluated the relationship between PTEN expression and clinicopathologic parameters. PTEN, estrogen receptor (ER), PR, and bcl-2 and bax expressions were evaluated immunohistochemically, and AI was evaluated in hematoxylin and eosin (HE)-stained slides in 23 cyclical and 37 hyperplastic endometria and in 35 EECs. PTEN expression was higher in cyclical endometrium than in the carcinomas (p<0.05). The PTEN expression level was significantly higher in non-atypical hyperplasias than in EEC, but there were no differences between atypical complex hyperplasia (ACH) and EEC and between hyperplasias. In the carcinomas, there was a negative correlation between grade and PTEN expression (r=-0.338, p=0.047). In conclusion, we presume that PTEN is involved in the early phases of endometrial tumorigenesis, and it can be speculated that decreased PTEN expression with loss of differentiation in carcinoma can contribute to the emergence of tumors with a more aggressive phenotype.
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PMID:Immunohistochemical expression of PTEN in normal, hyperplastic and malignant endometrium and its correlation with hormone receptors, bcl-2, bax, and apoptotic index. 1731 31

Endometrial carcinoma, endometrial stromal tumours and mixed malignant mesodermal tumours (MMMT) develop along distinctive molecular genetic pathways. Two distinctive types of endometrial carcinoma are distinguished, type I and type II, which develop along distinctive pathways and show different clinical behaviour and histological features. Type I carcinomas show endometrioid histology, are oestrogen-related and develop from atypical endometrial hyperplasia. The molecular tumorigenesis is comparable to colorectal carcinoma with a step-like progression and an accumulation of genetic alterations. Alterations of PTEN, K-Ras mutations and microsatellite instability are frequent and early events in type I carcinoma, whereas p53 mutations occur during progression to grade 3 carcinoma. Serous and clear cell carcinomas are considered type II carcinomas which are mostly unrelated to oestrogen. p53 mutations occur in almost all serous carcinomas and seem to occur early, leading to massive chromosomal instability and rapid tumour progression. Gene expression profiling has supported this dualistic model of endometrial carcinoma. There is evidence of molecular differences between serous and clear cell carcinomas as well as between endometrioid carcinomas with and without microsatellite instability. A dualistic model of tumorigenesis may be also suggested for endometrial stromal tumours. Endometrial stromal sarcomas (ESS; type I endometrial sarcoma) are oestrogen-related and seem to develop from endometrial stromal nodules (ESN). They are histologically and genetically distinct from undifferentiated endometrial sarcoma (UES) which seem to be mostly unrelated to oestrogen (type II endometrial sarcoma). ESS and ESN share the fusion gene JAZF1/JJAZ1 caused by a t(7;17)(p15;q21) translocation, whereas UES lacks a distinctive molecular alteration so far. In MMMT, which is considered a metaplastic carcinoma, p53 alteration occurs early, before clonal expansion and acquisition of genetic diversity during progression.
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PMID:Molecular genetic changes in epithelial, stromal and mixed neoplasms of the endometrium. 1736 22

In 1983, Bokhman proposed a dualistic model of endometrial tumorigenesis based on the clinical observations and clinicopathologic correlations. The majority of endometrial cancers (approximately 70-80%), designated as type I carcinomas, follow the estrogen-related pathway. Histologically, most of the type I tumors seem to arise in the background of hyperplastic endometrium, show an endometrioid differentiation, and are of low grade. Clinically, they are overall characterized by a favorable behavior. Another 10-20% of endometrial cancers, designated as type II carcinomas, follow the estrogen-unrelated pathway and arise in the background of atrophic endometrium. Type II tumors usually occur at an older age, approximately 5-10 years later than type I tumors. They are typically high-grade carcinomas of nonendometrioid differentiation, most frequently serous, less frequently clear cell. Type II carcinomas behave as an aggressive clinical course and poor prognosis. This dualistic model was subsequently supported by the molecular studies, approximately a decade later. At present, endometrioid and serous carcinoma, which represent the major phenotypes of types I and II endometrial carcinomas, respectively, are characterized by distinctive types of genetic instability and molecular alterations. In endometrioid (type I) carcinoma, four major genetic changes are responsible for the tumorigenesis, i.e. silencing of PTEN tumor suppressor gene, presence of microsatellite instability due to alterations of the mismatch repair genes, mutation of K-ras protooncogene, and alteration of beta-catenin gene. On the other hand, p53 mutation and overexpression of Her2/neu oncogene are two major genetic alterations in serous and clear cell (type II) carcinomas. However, like in any model, there is evidence for exceptions. Many endometrial carcinomas are in the gray zone with overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II endometrial cancers. Finally, a small group of endometrial carcinoma is noted to be hereditary. It is known as the most common extracolonic malignancy in hereditary nonpolyposis colorectal cancer (Lynch syndrome), an autosomal dominantly inherited disorder of cancer susceptibility. Inactivation of the mismatch repair genes MSH2 and MSH6 seems to play a central role in the tumorigenesis.
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PMID:Molecular carcinogenesis of endometrial cancer. 1738 85

Uterine serous papillary carcinoma (USPC) is a rare and highly malignant form of endometrial cancer (EC) characterized by early metastasis, chemoresistance, and high mortality rate. Little is known about USPC tumorigenesis even if recently a HER-2/neu role has been suggested in its development and progression. The aim of the present study was to evaluate HER-2 expression by immunohistochemistry (IHC) in 12 USPC formalin-fixed, paraffin-embedded (FFPE) samples. Moreover, we looked at the correlation between HER-2 protein expression and HER-2/neu gene amplification by fluorescence in situ hybridization (FISH), other than HER-2/neu messenger RNA expression by quantitative real-time reverse transcription (RT)-polymerase chain reaction (PCR). Finally, these results have been compared with commonly evaluated clinical features in EC patients, in order to define the potential prognostic value of HER-2/neu overexpression in USPCs. A high expression of HER-2 protein by IHC was noted in 2 of 12 patients (16.6%), and the same cases showed specific HER-2/neu gene amplification by FISH. All the samples investigated displayed a perfect concordance between IHC and FISH data. Five (41.6%) of 12 tumors demonstrated polysomy of chromosome 17 and, focusing on the 2 USPCs that showed HER-2/neu overexpression, one of them (50%) was polysomic for chromosome 17. All the other USPC cases (58.4%) showed to be disomic for chromosome 17. Quantitative RT real-time PCR performed on complementary DNA obtained from all FFPE USPC samples showed a complete correlation with FISH and IHC data. Moreover, HER-2/neu overexpression was associated with a poorer overall survival and a very low relapse-free survival time, thus being considered a candidate marker of worse overall prognosis in USPC. The use of trastuzumab (Herceptin), a monoclonal antibody directed against HER-2/neu, for the therapy of patients with HER-2/neu-positive USPCs should be further investigated in clinical trials.
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PMID:HER-2/neu overexpression and amplification in uterine serous papillary carcinoma: comparative analysis of immunohistochemistry, real-time reverse transcription-polymerase chain reaction, and fluorescence in situ hybridization. 1745 61

Hormone replacement therapy (HRT) has become available over the past few decades, but the risk of breast cancer with HRT remains controversial. The Women's Health Initiative Study has recently demonstrated that women receiving estrogen plus progestin (HRT) have an increased risk of invasive breast carcinoma, although women receiving estrogen alone (estrogen replacement therapy) exhibit no increased risk of breast carcinoma. By contrast, the risk of endometrial carcinoma increases with estrogen replacement therapy, while HRT reduces the risk of endometrial carcinoma. These clinical findings suggest that the biological roles of estrogen and progestin in tumorigenesis are certainly different between the endometrium and breast, although both are considered "estrogen-dependent tissues". In this review, I summarize the recent studies and indicate that the enzymes responsible for intratumoral estrogen metabolism and biosynthesis are markedly different between human breast and endometrial carcinomas. 17beta-hydroxysteroid dehydrogenases (17-HSDs) are enzymes estrogen replacement therapyinvolved in the formation of active sex steroids. Estrogens are interconverted by two enzymes, 17-HSD types 1 and 2. Type 1 converts estrone to estradiol, and type 2 catalyzes the reverse reaction. 17-HSD type 5 reduces androstenedione to testosterone. 17-HSD type 1 plays an important role in the regulation of high estradiol levels in breast carcinoma tissues, whereas 17-HSD types 2 and 5 appear to be essential for the maintenance of estradiol concentrations in endometrial carcinoma tissues. In addition, the biological significance of progesterone receptor isoforms differs between endometrial and breast carcinomas. These findings may provide new insights into the biology of "estrogen-dependent tissues".
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PMID:Hormone replacement therapy and cancers: the biological roles of estrogen and progestin in tumorigenesis are different between the endometrium and breast. 1746 97

While the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is known to be activated in multiple sporadic cancers, the role of this pathway in familial tumors is mostly unknown. We searched for alterations in the catalytic domain of PI3K (PIK3CA), PTEN and KRAS, all of which may contribute to PI3K/AKT pathway activation, in a total of 160-familial colorectal (CRC) and endometrial carcinomas (EC), stratified by the presence vs. absence of germline mutations in DNA mismatch repair (MMR) genes. PIK3CA alterations (consisting of point mutations or low-level amplification, which were mutually exclusive with 1 exception) occurred in 10/70 (14%) of CRCs and 19/90 (21%) of ECs. Within ECs, amplification was significantly associated with the subgroup lacking germline mutations in MMR genes (familial site-specific endometrial cancer) (p = 0.015). Decreased or lost PTEN expression was characteristic of endometrial tumourigenesis (51/81, 63%, in EC compared with 24/62, 39%, in CRC, p = 0.004) and KRAS mutations of colorectal tumourigenesis (19/70, 27% in CRC vs. 9/89, 10%, in EC, p = 0.006) regardless of the MMR gene mutation status. PIK3CA alterations frequently coexisted with PTEN or KRAS changes. Combined with published studies on sporadic tumors, our data broaden the understanding of the role for PI3K pathway genes in human tumorigenesis.
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PMID:Patterns of PIK3CA alterations in familial colorectal and endometrial carcinoma. 1747 59


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