Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

The p53 gene is altered in approximately 50% of human cancers and is considered to be important in the pathogenesis of these malignancies. The p53 protein product regulates the transition from G1 to S phase of the cell cycle and entry to the DNA damage repair pathway. As alterations in this pathway appear to be important in a variety of human cancers, downstream effector proteins of p53 are potential sites for somatic alterations. WAF1/Cip1, also known as WAF1, Cip1, sdi1, or CAP20, codes for a 21-kd protein (p21WAF1/Cip1), which was recently described as a universal inhibitor of cyclins and is thus critical in cell cycle control. Mutations in WAF1/Cip1 are potentially important in human malignancies because they could affect the control of the cell cycle. To understand whether mutations of WAF1/Cip1 occur in cancer, we screened 53 cases of invasive breast carcinoma, 35 cases of ductal carcinoma in situ (DCIS), 53 ovarian carcinomas, and 47 endometrial carcinomas in the second exon of WAF1/Cip1 (90% of the open reading frame). p21WAF1/Cip1 expression was characterized with immunohistochemistry. Cells from the blood of 21 normal individuals were also characterized using single-strand conformational polymorphism analysis, DNA sequencing and restriction analysis. Single-strand conformational polymorphism analysis demonstrated an altered mobility pattern for exon 2 in 12 invasive breast cancers (22.6%), 5 DCIS of the breast (14%), 8 invasive ovarian carcinomas (15%), and 9 endometrial carcinomas (19%). In total, 209 samples were screened, and 38 cases (18.2%) had an altered codon 31. Each case with altered single-strand conformational polymorphism, analyzed by DNA sequencing and/or restriction analysis, showed the same alteration of codon 31, a C to A transversion encoding a change in amino acid sequence from serine to arginine (31Ser-->31Arg). DNA from the blood of 21 normal individuals showed the same alteration in WAF1/Cip1 in 4 cases (19%). Furthermore, paired normal tissue was available for 3 of 20 breast carcinomas with the Ser31Arg transversion. Normal DNA from all 3 cases showed the same 31Arg alteration as found in the tumor tissue. These results indicate that codon 31 is a polymorphic site and that the serine to arginine shift is a polymorphism. p21WAF1/Cip1 expression, identified by immunohistochemistry, was found to vary in a pattern that depended both on the tissue type and on the presence or absence of the codon 31 polymorphism. Using pair-wise comparisons in breast DCIS, we found higher protein expression in tumor nuclei as compared with benign stromal cell nuclei (P = 0.002) or normal ductal epithelium (P = 0.005). Invasive breast cancer specimens showed a trend in p21WAF1/Cip1 immunostaining similar to DCIS but did not reach statistical significance (P = 0.12). However, when cases with extensive desmoplastic reaction were excluded, a statistically significant association (P = 0.019) similar to that in DCIS was noted. In contrast to the breast tumors, ovarian carcinomas exhibited significantly greater p21WAF1/Cip1 expression in the benign stromal (fibroblast) nuclei surrounding the tumor than in the carcinoma cell nuclei (P = 0.016). Endometrial carcinoma revealed no difference in staining when comparing benign tissue with carcinoma (P = 0.99); however, unlike breast and ovarian carcinomas in which there was no correlation between p21WAF1/Cip1 expression and the presence or absence of the alteration at the 31st codon, endometrial carcinomas showed an increased percentage of immunopositive nuclei associated (P = 0.056) with 31Arg. These results demonstrate tissue-specific expression patterns of WAF1/Cip1 in different tumors which appears to be characteristic of the tumor type.
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PMID:WAF1/Cip1 gene polymorphism and expression in carcinomas of the breast, ovary, and endometrium. 900 33

Beta-catenin forms complexes with Tcf and Lef-1 and functions as a transcriptional activator downstream of the Wnt signaling pathway. Activation of the pathway by stabilization of beta-catenin has been shown to be important in the development of colorectal carcinoma, which is mainly caused by inactivating mutations of the adenomatous polyposis coli tumor suppressor gene or by activating mutations in exon 3 of the beta-catenin gene. Here, we analyzed mutations in exon 3 of the beta-catenin gene in endometrial carcinoma cases in which loss of heterozygosity at the adenomatous polyposis coli tumor suppressor gene locus has been rarely reported. We found that 10 of 76 cases had beta-catenin gene mutations. All mutations identified were single-base missense mutations on serine/threonine residues (codons 33, 37, 41, and 45), altering the glycogen synthase kinase-3beta phosphorylation consensus motif, which participates in the degradation of beta-catenin. To determine whether these beta-catenin mutations actually led to stabilization of this protein, expression of beta-catenin was analyzed immunohistochemically, and 9 of 10 cases with the beta-catenin mutation and 20 of 66 cases without it showed accumulation of beta-catenin in the cytoplasm and/or nucleus. In total, 38% of cases showed accumulation of beta-catenin. These data indicate that stabilization of beta-catenin due to mutations in exon 3 of the beta-catenin gene and other mechanisms may have an important role in development of endometrial carcinomas.
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PMID:Beta-catenin mutation in carcinoma of the uterine endometrium. 972 53

The WAF1 protein, which is a downstream mediator of p53, functions as a universal inhibitor of cyclin-dependent kinases. The functional link between p53 and WAF1 suggests the possibility that alteration in WAF1 function constitutes an alternative mechanism to p53 inactivation. However, there are few reports describing somatic mutations of the WAF1 gene in various human malignancies. A polymorphism in the WAF1 gene, a C-to-A transversion at codon 31 resulting in the change of a serine (Ser) to an arginine (Arg), is well known. We found this substitution in 42 of 54 endometrial carcinoma patients. Allele frequency was 0.44/0.56 for the codon 31 polymorphism (Ser/Arg), the difference of allele frequency between patients and normal controls being significant (0.59/0.41 in normal controls). In addition, individuals carrying the codon 31 Arg allele had a tendency to develop histologically high-grade (odds ratio, 6. 11) and clinically advanced tumors. We investigated the association of the Arg allele with the known risk factors of endometrial carcinomas. Statistical analyses of 42 cases and 32 controls carrying the codon 31 Arg allele identified hypertension (odds ratio, 4.33) and family history of cancer (odds ratio, 2.81) as positive risk factors. This implies that these two parameters may be associated with a tendency to develop endometrial carcinomas in individuals carrying the codon 31 Arg allele of the WAF1 gene.
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PMID:WAF1 genotype and endometrial cancer susceptibility. 1002 Dec 99

To investigate the contribution of beta-catenin to the development of endometrial carcinoma, we searched for genetic alterations of the beta-catenin gene in primary endometrial carcinomas. Mutational analysis of exon 3 of the beta-catenin gene, encoding the serine/threonine residues for GSK-3 beta phosphorylation, was performed for 35 tumors. Nucleotide sequencing analysis revealed that 5 tumors (5/35, 14%) contained mutations (S33C, S37C, S37F, T41A) that altered potential GSK-3 beta phosphorylation sites. Each of the mutations resulted in the substitution of serine/threonine residues that have been implicated in the down-regulation of beta-catenin through phosphorylation by GSK-3 beta kinase. Furthermore, the incidence of beta-catenin mutations was significantly higher in early-onset (3 of 5) than that in late-onset tumors (2 of 30) (P = 0.014, Fisher's exact test). Replication error (RER)-positive phenotype was not detected in tumors with the beta-catenin gene mutation, although 10 of 35 tumors revealed RER. We performed immunohistochemistry of beta-catenin in 17 cases for which tissue samples were available. We confirmed accumulation of beta-catenin protein in both the nucleus and cytoplasm in 3 tumors, including two in which amino acid alterations had occurred at codon 33 and 37. The other case had no mutation in exon 3. Our results suggested that mutations at serine/threonine residues involved in phosphorylation by GSK-3 beta affected the stability of beta-catenin. Accumulation of mutant beta-catenin could contribute to the development of a subset of endometrial carcinomas, particularly those of the early-onset type.
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PMID:Mutations of the beta-catenin gene in endometrial carcinomas. 1007 65

The human tissue kallikrein (KLK) family of serine proteases, which is important in post-translational processing events, currently consists of just three genes-tissue kallikrein (KLK1), KLK2, and prostate-specific antigen (PSA) (KLK3)-clustered at chromosome 19q13. 3-13.4. We identified an expressed sequence tag from an endometrial carcinoma cDNA library with 50% identity to the three known KLK genes. Primers designed to putative exon 2 and exon 3 regions from this novel kallikrein-related sequence were used to polymerase chain reaction-screen five cosmids spanning 130 kb around the KLK locus on chromosome 19. This new gene, which we have named KLK4, is 25 kb downstream of the KLK2 gene and follows a region that includes two other putative KLK-like gene fragments. KLK4 spans 5.2 kb, has an identical genomic structure-five exons and four introns-to the other KLK genes and is transcribed on the reverse strand, in the same direction as KLK1 but opposite to that of KLK2 and KLK3. It encodes a 254-amino acid prepro-serine protease that is most similar (78% identical) to pig enamel matrix serine protease but is also 37% identical to PSA. These data suggest that the human kallikrein gene family locus on chromosome 19 is larger than previously thought and also indicate a greater sequence divergence within this family compared with the highly conserved rodent kallikrein genes.
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PMID:Localization of a new prostate-specific antigen-related serine protease gene, KLK4, is evidence for an expanded human kallikrein gene family cluster on chromosome 19q13.3-13.4. 1043 93

Local invasiveness is an important prognostic factor in endometrial carcinoma. To study the role of two groups of secreted proteinases (serine proteinases and matrix metalloproteinases) in this process, we examined three endometrial cancer cell lines (Ishikawa HEC 1A, AN3CA) for their invasiveness in vitro. Additionally, we considered the secretion of urokinase type plasminogen activator (uPA), plasminogen activator inhibitor 1 and 2 (PAI-1 and PAI-2), as well as matrix metalloproteinases (MMP) 1, 2, 3, and 9, and their inhibitors TIMP-1 and TIMP-2. Compared to the highly invasive fibrosarcoma cell line HT 1080, Ishikawa displayed low and AN3CA moderate invasiveness, while HEC 1A cells were almost as invasive as HT 1080 cells. Ishikawa cells secreted the highest amounts of proteinases. Cytokine and steroid treatments upregulated MMP-1 in all cell lines while the effects were heterogeneous regarding other proteinases and inhibitors. No effect of these treatments on invasiveness could be detected. Both basal secretion and regulation of the proteinases tested in this set of experiments seem to be markers of differentiation rather than of invasiveness.
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PMID:Invasiveness corresponds to differentiation rather than to proteinase secretion in endometrial cancer cell lines. 1060 96

Endometrial cancer is the fourth most common female malignancy in women in developed countries. Estrogen, and to a lesser degree, progesterone, regulate specific target genes that are involved in endometrial tumorigenesis. A family of proteases involved in cellular proliferation, extracellular matrix degradation and thus, implicated in tumorigenesis, and regulated by estrogen and progesterone in a number of systems, are the tissue kallikreins (KLKs). KLK4, a new member of the KLK gene family, was found to be expressed to varying levels in a number of endometrial cancer cell lines- HEC1A, HEC1B, Ishikawa, RL95-2 and KLE- at both the mRNA and protein level. On the addition of 10 nmol/L estradiol, progesterone, or a combination of both over a 48 h period, an increase in the intracellular protein levels of K4 were observed when compared to the control (untreated) cells. We have also identified a novel KLK4 transcript with a complete exon 4 deletion. The significance of this alternative transcript, which would give rise to a truncated protein without a serine residue (which is essential for catalytic activity), is yet to be established. These cell lines now provide a model system to study the role of KLK4 and the molecular mechanisms of KLK4 regulation by estrogen and progesterone, in endometrial tumorigenesis.
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PMID:Kallikrein 4 (KLK4), a new member of the human kallikrein gene family is up-regulated by estrogen and progesterone in the human endometrial cancer cell line, KLE. 1134 46

beta-Catenin gene mutations and microsatellite instability (MI) have been reported in endometrioid ovarian carcinomas. In colon but not endometrial cancer, beta-catenin gene mutations are associated with a replication error phenotype and MI. In this study the authors investigate whether beta-catenin mutations and MI are two independent oncogenic pathways in endometrioid ovarian carcinomas. They also evaluate the usefulness of these molecular markers in determining the primary origin of simultaneous tumors in the ovary and endometrium. This study was performed on 26 patients diagnosed with primary endometrioid ovarian carcinoma, five of whom also had pathologically diagnosed primary synchronous endometrioid endometrial carcinoma. Immunohistochemical and molecular analyses indicated that there were 25 primary ovarian tumors with four primary synchronous endometrial cancers and one ovarian metastasis of a primary endometrial carcinoma. All studies were performed on formalin-fixed, paraffin-embedded tissue samples. The beta-catenin expression pattern (nuclear vs. membranous) was analyzed immunohistochemically. Mutations in exon 3 of the beta-catenin gene were studied by polymerase chain reaction, single-strand conformational polymorphism, and direct sequencing. MI status was established by studying BAT-26 and BAT-25 mononucleotide repeats. In the group with 21 single ovarian tumors, 18 (85%) had beta-catenin nuclear expression, eight (38%) had beta-catenin gene mutations (always associated with beta-catenin nuclear expression), and four (19%) had MI. Only one case (5%) had both beta-catenin gene mutations and MI. The mutations affected one of the serine/threonine residues targeted for phosphorylation by glycogen synthase kinase-3beta or adjacent residues. At codon 32, a GAC-to-TAC (D32Y) change was found; at codon 33, two TCT-to-TGT (S33C) changes were found; at codon 37, three TCT-to-TTT (S37F) changes and one TCT-to-TGT (S37C) change were found; and, lastly, one ACC-to-GCC change at codon 41 (T41A) was detected. Four of the 25 endometrioid ovarian carcinomas (16%) had an associated synchronous endometrial carcinoma. There was a higher percentage of beta-catenin mutations (n = 3, 75%) in synchronous ovarian carcinomas than in single ones, although with a similar percentage of MI (n = 1, 25%). beta-catenin mutations were S37C in two cases and D32G in one. One of the four endometrial carcinomas showed an S33C beta-catenin mutation, and two carcinomas had MI. None of the four tumors had both beta-catenin gene mutation and MI. beta-catenin gene mutations were always associated with a nuclear beta-catenin expression pattern, whereas MI was associated with a membranous pattern. In one patient both the ovarian and the endometrial carcinomas had beta-catenin gene mutations, in another patient both tumors showed MI, whereas in the remaining two patients the ovarian carcinomas showed beta-catenin gene mutations and the endometrial carcinomas showed MI. To summarize, the results of this study suggest that beta-catenin mutations and MI could represent two independent pathways in endometrioid ovarian carcinomas because they occur simultaneously very infrequently (in 5% of these cases). beta-catenin mutations are always associated with a nuclear beta-catenin expression pattern, whereas cases with a replication error -plus phenotype showed no abnormal beta-catenin subcellular localization. The study of the beta-catenin expression pattern, beta-catenin mutations, and MI, together with conventional clinicopathologic findings, could aid in distinguishing between the metastatic or independent origin of simultaneous endometrioid ovarian and endometrial carcinomas. Tumors with identical immunohistochemical and molecular features should therefore be considered to have a common origin.
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PMID:beta-Catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas. 1138 21

Tamoxifen is the most widely used selective estrogen receptor modulator for breast cancer in clinical use today. However, tamoxifen agonist action in endometrium remains a major hurdle for tamoxifen therapy. Activation of the nonreceptor tyrosine kinase src promotes tamoxifen agonist action, although the mechanisms remain unclear. To examine these mechanisms, the effect of src kinase on estrogen and tamoxifen signaling in tamoxifen-resistant Ishikawa endometrial adenocarcinoma cells was assessed. A novel connection was identified between src kinase and serine 167 phosphorylation in estrogen receptor (ER)-alpha via activation of AKT kinase. Serine 167 phosphorylation stabilized ER interaction with endogenous ER-dependent promoters. Src kinase exhibited the additional function of potentiating the transcriptional activity of Gal-steroid receptor coactivator 1 (SRC-1) and Gal-cAMP response element binding protein-binding protein in endometrial cancer cells while having no effect on Gal-p300-associated factor and Gal fusions of the other p160 coactivators glucocorticoid-interacting protein 1 (transcriptional intermediary factor 2/nuclear coactivator-2/SRC-2) and amplified in breast cancer 1 (receptor-associated coactivator 3/activator of transcription of nuclear receptor/SRC-3). Src effects on ER phosphorylation and SRC-1 activity both contributed to tamoxifen agonist action on ER-dependent gene expression in Ishikawa cells. Taken together, these data demonstrate that src kinase potentiates tamoxifen agonist action through serine 167-dependent stabilization of ER promoter interaction and through elevation of SRC-1 and cAMP response element binding protein-binding protein coactivation of ER.
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PMID:The Src kinase pathway promotes tamoxifen agonist action in Ishikawa endometrial cells through phosphorylation-dependent stabilization of estrogen receptor (alpha) promoter interaction and elevated steroid receptor coactivator 1 activity. 1552 70

Matrix metalloproteinase-7 (MMP-7) is upregulated during carcinogenesis and its expression correlates with metastasis of human endometrial and gastrointestinal carcinomas. In the present study, we have developed a new method to localize the activity of MMP-7 within tissues. Polyethylene terephthalate films were uniformly coated with crosslinked carboxymethylated transferrin (CCm-Tf) as a substrate and incubated with frozen tissue sections mounted on the films. CCm-Tf on the films was degraded selectively by MMP-7, but showed little or no susceptibility to MMP-1, -2, -3, -9, or -13; MT1-MMP; MT3-MMP; or ADAMTS4. Although some serine proteinases such as elastase also digested CCm-Tf, CCm-Tf films impregnated with serine proteinase inhibitors prevented the digestion. When frozen sections of human endometrial carcinoma and lung carcinoma tissues were incubated on CCm-Tf films or those treated with proteinase inhibitors, the activity was detected in the carcinoma cell nests, where MMP-7 was immunolocalized. The present in situ zymography using CCm-Tf may be a useful method to analyze the functions of MMP-7 in pathophysiological conditions.
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PMID:Development of in situ zymography to localize active matrix metalloproteinase-7 (matrilysin-1). 1595 27


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