Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Few biological parameters have been shown to have a prognostic role in patients with advanced ovarian cancer. p27Kip1 is a cyclin-dependent kinase inhibitor, and its loss may contribute to tumor progression. We determined whether p27Kip1 protein expression in advanced ovarian cancer could be associated with prognosis. p27Kip1 status was assessed by immunohistochemical analysis of tissue sections from primary tumors of 99 patients with stages III-IV ovarian carcinoma and was analyzed in relation to clinicopathological variables, time to progression (TTP), and overall survival (OS). p27Kip1 expression was detected in 47 (47%) of the 99 patients. p27 expression did not correlate with any of the classical clinicopathological parameters. Loss of p27 protein was significantly associated with a short TTP (P = 0.0004) and decreased OS (P = 0.0302). The 5-year TTP rate in p27-positive patients was 50% versus 11% in p27-negative patients. p27-positive cases showed a 5-year OS rate of 53% compared with 43% of p27-negative cases. In multivariate analysis, p27 expression was an independent predictor of progression of disease (P = 0.0009) and survival (P = 0.0032) when considered together with stage of disease, presence of ascites, and residual tumor at surgery. Loss of p27Kip1 conferred poor prognosis independently of proliferative index, as assessed by proliferating cell nuclear antigen immunostaining. p27 immunoreactivity can be used to predict progression of disease and survival in patients with advanced epithelial ovarian cancer and therefore may represent a new prognostic marker.
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PMID:p27Kip1 expression is associated with clinical outcome in advanced epithelial ovarian cancer: multivariate analysis. 1115 40

To identify changes in gene expression with transformation and metastasis, we investigated differential gene expression in a squamous carcinoma model established in syngeneic mice. We used mRNA differential display (DD) to detect global differences and cDNA arrays enriched for cancer-associated genes using mRNA from primary keratinocytes, transformed Pam 212 squamous carcinoma cells, and metastases of Pam 212. After DD, 72 candidate cDNAs expressed primarily in transformed and metastatic cells were selected and cloned. Fifty-seven were detected, and 32 were confirmed to be differentially expressed by Northern blot analysis. mRNA expression profiles were also generated using a mouse cDNA array composed of 4000 elements representing known genes and expressed sequence tags plus the 57 DD candidate cDNAs detected by Northern analysis to facilitate data validation. cDNA array detected 76.9% of the differentially expressed mRNAs selected from DD and confirmed by Northern blot, whereas low-abundance mRNAs did not reach the threshold for detection by the lower-sensitivity array method. Clustering analysis of DD and array results from transformed and metastatic cells identified genes that exhibited decreased or increased expression with transformation and metastasis. Alterations in the expression of several genes detected during tumor progression were consistent with their functional activities involving growth (p21, p27, and cyclin D1), resistance and apoptosis (glutathione-S-transferase, cIAP-1, PEA-15, and Fas ligand), inflammation and angiogenesis [chemokine growth-regulated oncogene 1 (also called KC)], and signal transduction (c-Met, yes-associated protein, and syk). Strikingly, 10 of 22 genes in the cluster expressed in metastases have been associated with activation of the nuclear factor (NF)-kappaB signal pathway. The NF-kappaB-inducible cytokine Gro-1 was recently shown to promote tumor growth, metastasis, and angiogenesis of squamous cell carcinomas in vivo (Loukinova et al., Oncogene, 19: 3477-3486, 2000). The results demonstrate that early response genes related to NF-kappaB contribute to metastatic tumor progression. Comparison of cell lines and tumor tissue revealed a concordance of approximately 50% by array, and 70% for Northern-confirmed, metastasis-related genes. Functional genomic approaches comparing expression among cell lines and tumor tissue may promote a better understanding of the genes expressed by malignant and host cells during tumor progression and metastasis.
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PMID:Molecular profiling of transformed and metastatic murine squamous carcinoma cells by differential display and cDNA microarray reveals altered expression of multiple genes related to growth, apoptosis, angiogenesis, and the NF-kappaB signal pathway. 1140 55

p27 is a cyclin-dependent kinase inhibitor which regulates progression of cells from G1 into S phase in a cell cycle. Loss of the negative regulator may contribute to oncogenesis and tumor progression. The aim of this study was to examine p27 expression in normal mucosa, primary and metastatic tumors from patients with colorectal adenocarcinomas and to analyze association of p27 with patient survival and clinicopathological variables. p27 expression was estimated by immunohistochemistry in 178 primary colorectal cancers, 34 lymph node metastases and 48 normal mucosa samples from patients with colorectal adenocarcinoma. Associations of p27 with patient survival, clinicopathological characteristics and expression of p53, p73 and DCC were analyzed. Loss of p27 was found in 51% of primary tumors, 68% of metastases and 56% of normal samples. The intensity of p27 staining was similar in the matched primary tumor, metastasis and normal mucosa. In patients with Dukes' B or with proximal tumors, the loss of p27 predicted poorer prognosis (p = 0.03 and p = 0.05, respectively). However, there were no significant differences in the patients with other individual Dukes' stage or distal tumors. No relationships were found between p27 and patients' gender, age, tumor location, growth pattern and expression of p53, p73 and DCC (p > 0.05). The data suggest that loss of p27 was associated with poor prognosis in patients with Dukes' B tumor or those with proximal tumor. p27 might be a useful marker to identify the more progressive tumors in these groups.
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PMID:Loss of p27 expression predicts poor prognosis in patients with Dukes' B stage or proximal colorectal cancer. 1140 21

Different studies have already shown that the isolated inactivation of p21, p16, or p27 cyclin-dependent kinase inhibitors (CKIs) is associated with increased growth fraction, tumor progression, or decreased overall survival in cases of non-Hodgkin's lymphoma. In this study we linked molecular study of the p53 and p16 genes with immunohistochemical analysis of p27 expression in a group of aggressive B-cell lymphomas [large B-cell lymphomas (LBCLs) and Burkitt's lymphomas]. This was done to analyze the relationship between p53 and p16 silencing, p27 anomalous overexpression, and clinical follow-up, testing the hypothesis that the accumulation of CKI alterations could confer to the tumors a higher aggressivity. In a group of 62 patients, p53 inactivation as a result of mutation was observed in 11 cases (18%) and p16 silencing was seen in 27 cases (43.5%) as a result of methylation (20 of 62), 9p21 deletion (7 of 44), or p16 mutation (2 of 62). The simultaneous inactivation of p53 and p16 was detected exclusively in five LBCL cases. Anomalous expression of p27, which has been proven to be associated with the absence of p27/CDK2 complexes and the formation of p27/cyclin D3 complexes where p27 is inactivated, was detected in 19 of 61 cases (31%). Cases characterized by p27 anomalous expression display concurrent inactivation of p21 (provided by p53 mutations) and/or p16 CKIs in 11 of 14 LBCL cases (P = 0.040). When the relationship between the association of inactivated CKIs and overall survival was considered, a significant relationship was found between a lower overall survival probability and an increased number of inactivated CKIs in LBCL cases, with the worst prognosis for the cases displaying concurrent p53, p16, and p27 alterations. This proves that simultaneous inactivation of different tumor suppressor pathways does indeed take place, and that tumor aggressiveness takes advantage of this CKI-concerted silencing. In this same series of data, Burkitt's lymphoma patients seem to behave in a different way than LBCLs, with p53 and p16 alteration being mutually exclusive and the association with p27 anomalous expression not being clinically significant. These facts seem to support that the additive effect of the inactivation of different CKIs could be dependent of the histological type.
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PMID:Overall survival in aggressive B-cell lymphomas is dependent on the accumulation of alterations in p53, p16, and p27. 1143 67

In order to evaluate biological and genetic properties of early breast carcinomas we analyzed microdissected tissue from 33 primary breast carcinomas stage T1b and T1c with respect to the nuclear DNA content, the expression pattern of Ki-67, cyclin A, p27KIP1, p53 and p21WAF1, and chromosomal gains and losses. The results show that T1b carcinomas (6-10 mm, n=17) were frequently near-diploid (53%) with low proliferative activity and staining patterns of p53 and p21WAF1 that suggest the presence of wild type protein. The majority (12/16) of the T1c tumors (11-20 mm), however, was aneuploid, and proliferative activity and p53 expression were increased. Larger tumor size correlated with an increasing number of chromosomal copy number changes and in particular with regional amplifications. High level copy number increases (amplifications), however, were found exclusively in the aneuploid tumors. Amplification events correlated with elevated cyclin A and reduced p27 expression, respectively. Our results suggest that the sequential acquisition of genomic imbalances during tumor progression is accelerated in aneuploid tumors, and may contribute to the increased malignancy potential.
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PMID:Genetic instability promotes the acquisition of chromosomal imbalances in T1b and T1c breast adenocarcinomas. 1145 31

Previously, we have linked prolonged intense mitogen-activated protein kinase (MAP kinase; MAPK) signaling in hepatocytes to increased expression of p21(Cip-1/WAF1/MDA6) (p21) and p16(INK4a) (p16), that leads to a p21-dependent growth arrest. In this study, we investigated the impact of hepatitis B virus X protein (pX) expression on MAPK-modulated cell cycle progression in primary mouse hepatocytes. In hepatocytes, expression of pX enhanced protein levels of p21 and p27, but not of p16. The elevated levels of p21 and p27 correlated with reduced DNA synthesis in wild-type (+/+) hepatocytes and with a weak stimulation of DNA synthesis in p21 null (-/-) cells. Antisense p27 messenger RNA (mRNA) (p27as) increased DNA synthesis in +/+ and p21 -/- cells, and pX blunted this effect in +/+ cells. In p21 -/- cells, however, p27as permitted pX to further stimulate DNA synthesis. These data argue that a reduced ability to enhance expression of both p21 and p27 is required to fully reveal the growth-potentiating properties of pX. This finding also implies that depending on the functional status of the p21 and p27 genes, expression of pX can have 2 very different effects on hepatocyte proliferation. Prolonged intense MAPK signaling reduced DNA synthesis in +/+ cells and enhanced DNA synthesis in p21 -/- cells. The enhancement of DNA synthesis in p21 -/- cells was blocked by pX, and the effect of pX was abrogated by p27as. Furthermore in p21 -/- cells, overexpression of p16 blocked MAPK-stimulated DNA synthesis, and this effect was partially reversed by p27as. These data argue that p27 can also cooperatively interact with p16 to inhibit DNA synthesis in hepatocytes. Collectively, our findings show that reduced expression of p16, p21, and p27, which can occur during hepatocellular carcinoma, enhances the ability of MAPK signaling and pX to cause proliferation in hepatocytes. Thus loss of cyclin kinase inhibitor function may play an important role in the process of tumor progression after chronic hepatitis B virus infection.
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PMID:Hepatitis B virus X protein increases expression of p21(Cip-1/WAF1/MDA6) and p27(Kip-1) in primary mouse hepatocytes, leading to reduced cell cycle progression. 1167 61

Neoplastic progression in Barrett's esophagus is a multi-step process in which the metaplastic columnar epithelium sequentially evolves through a metaplasia-dysplasia-carcinoma sequence. The expression and DNA copy number of key cell cycle regulatory genes in paired normal and Barrett's esophagus samples was evaluated. Protein levels were evaluated in 60 formalin-fixed, paraffin-embedded human tissues by immunohistochemistry. DNA copy number from 20 fresh tissue pairs was analysed by Southern blot analysis. All normal mucosal samples expressed the p27(kip1) protein, but did not display appreciable nuclear staining for p16(kip4), p21(cip1) or cyclins D1 and E. Barrett's metaplastic specimens displayed increased expression levels of p16(kip4) (74%), p21(cip1) (89%) and cyclins D1 (43%) and E (37%). p27 protein was absent in three cases. There was a significant correlation between the expression of p16(kip4) and cyclin E, and p21(cip1) and p27(kip4) with cyclin D1. DNA analysis did not reveal any amplification or deletion of these genes. Acid suppression, however, was associated with significantly lower expression levels of key cell cycle proteins. Increased expression of key cell cycle regulatory genes appears to occur early in the neoplastic progression associated with Barrett's esophagus. Treatment with proton pump inhibitors appears to alter this increased expression.
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PMID:Proton pump inhibitors reduce cell cycle abnormalities in Barrett's esophagus. 1175 81

Cyclin D1 contributes to regulate G1 progression by forming a complex with different cyclin-dependent kinases. It has oncogenic properties and is frequently overexpressed in several human tumor types. In our study, expression of cyclin D1 and Ki67, a proliferation marker, was evaluated by immunohistochemistry in human papillary superficial (pTa-pT1) bladder cancers and was correlated with p27(Kip1), p21(Waf1) and c-erbB-2 expression, with p53 gene status and protein expression, ploidy and cancer progression. Cyclin D1 expression was neither associated with tumor stage nor with tumor grade but high cyclin D1 expression (> or =25% positive nuclei) was significantly associated with p53 gene mutation (p = 0.012), low p21(Waf1) (p = 0.015) and high p27(Kip1) (p = 0.016) protein expression. Ki67 expression was not associated with tumor stage but a high proliferation index (> or =10% positive nuclei) was significantly associated with high tumor grade (p = 0.001) and with DNA aneuploidy (p = 0.005). There was no significant difference in proliferative activity between high and low cyclin D1 expressor tumors. Patients whose tumors showed high expression of cyclin D1 displayed a significantly longer disease-free survival (p < 0.001 by log-rank test). Increased Ki67 expression was significantly associated with shorter disease-free survival (p = 0.003). Both cyclin D1 (p = 0.027; RR = 1.898) and Ki67 (p = 0.047; RR = 1.932) protein expressions were independent predictors of reduced disease-free survival on a multivariate analysis that also included p27(Kip1) expression and tumor stage. The simultaneous presence of low cyclin D1, low p27(Kip1) and high Ki67 expression defined a "high-risk" group of patients who displayed a significantly increased risk of recurrence (p < 0.0001). These results suggest that evaluation of cell cycle-associated markers can help to identify high-risk patients and may affect the management of patients with papillary superficial bladder cancer.
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PMID:Cyclin D1 expression in papillary superficial bladder cancer: its association with other cell cycle-associated proteins, cell proliferation and clinical outcome. 1180 96

The abundance of p27(Kip1), an inhibitor of cell proliferation, is determined by Skp2-dependent proteolysis, the deregulation of which is associated with cancer progression. Lack of Skp2 results in p27(Kip1) accumulation as well as enlargement and polyploidy of hepatocytes. The role of Skp2 in cell growth and proliferation was investigated in Skp2-deficient mice subjected to partial hepatectomy. Skp2(-/-) mice exhibited restoration of liver mass without cell proliferation; rather, hepatocytes increased in size, an effect that was accompanied by increased polyploidy and p27(Kip1) accumulation. Lack of Skp2 thus impairs hepatocyte proliferation, which is compensated for by cellular enlargement, during liver regeneration.
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PMID:Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2-deficient mice. 1186 71

To account for the accumulation of genomic alterations required for tumor progression, it has been suggested that the genomes of cancer cells are unstable and that this instability results from defective mutators (the "mutator phenotype" theory). To examine the hypothesis that abnormal cell-cycle regulators act as the mutators contributing to genomic instability, the present study, based on primary tumor tissues from 71 patients with breast cancer, was performed to determine whether there was an association between aberrant expression of cell-cycle regulators (cyclin A, cyclin D1, cyclin E, RB1, p21, and p27) and chromosomal instability. Comparative genomic hybridization was used to measure chromosomal changes, reflecting genomic instability in individual tumors, whereas immunohistochemistry was used to detect aberrant expression of cell-cycle regulators. Overexpression of cyclin D1 was found to be significantly correlated with increased chromosomal instability (defined as harboring more than 7 chromosomal changes), with 63% of tumors overexpressing and 27% of tumors not overexpressing, with cyclin D1 showing chromosomal instability (P < 0.05). Interestingly, this relationship was independent of cell outgrowth (as detected by the proliferation marker Ki-67) and was particularly significant in tumors not expressing p27 or in tumors with detectable RB1. These results suggest that cyclin D1 plays an alternative role in the regulation of genomic stability.
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PMID:Aberrant expression of cell-cycle regulator cyclin D1 in breast cancer is related to chromosomal genomic instability. 1200 88


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