Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deregulation of G1 cyclins has been reported in several human and rodent tumors including colon cancer. To investigate the expression pattern of G1 cyclins in 1,2- dimethyl-hydrazine dihydrochloride (DMH)-induced rat colon carcinogenesis, we studied the expression of cyclin D1 and cyclin E by quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis and immunohistochemistry (IHC). The mRNA level of cyclin D1 was increased 1.2-fold in adenocarcinomas but not significantly in adenomas, when compared with normal rat colonic mucosa (p<0.05). The cyclin E mRNA level was increased 2.7-fold in adenomas and 3.3-fold in adenocarcinomas (p<0.05). The PCNA mRNA level was also increased 1.9-fold in adenomas and 1.8-fold in adenocarcinomas (p<0.05). Immunohistochemical staining revealed exclusive nuclear staining of the neoplastic cells for cyclin D1, cyclin E and PCNA. Cyclin D1 expression was detected in 56.3% of the adenomas and in 61.5% of the adenocarcinomas examined, whereas cyclin E expression was detected in 87.5% of the adenomas and in 92.3% of the adenocarcinomas. Overall, cyclin D1, cyclin E and PCNA expression was significantly increased at both the mRNA and protein levels in normal colonic mucosa, adenomas and adenocarcinomas, but there was no significant difference in the degree of expression of these genes in adenomas and adenocarcinomas. Our results indicate that the overexpression of cyclin D1 and cyclin E may play an important role during the multistage process of rat colon carcinogenesis, at a relatively early stage, and may disturb cell-cycle control in benign adenomas, and thereafter, participate in tumor progression.
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PMID:Overexpression of cyclin D1 and cyclin E in 1,2-dimethylhydrazine dihydrochloride-induced rat colon carcinogenesis. 1461 7

The retinoblastoma (Rb) pathway controls the G1-S checkpoint of the cell cycle. Inactivating mutations and deletions of p16 and Rb and up-regulation of cyclin D1 disrupt this pathway and occur in many cancers. However, the concurrent expression of these genes in primary and metastatic gastric cancer is unknown, and the prognostic value of their expression is unclear. In this study, the expression of cyclin D1, retinoblastoma protein (pRb), and p16 in 67 resected gastric adenocarcinomas, and of pRb and p16 in 40 associated lymph node metastases, was determined using a streptavidin-biotin-peroxidase immunohistochemical method. Relationships with clinical and pathological features were analyzed. Cyclin D1 overexpression (>/=5% expression) was seen in 55% of cancers; pRb loss (<20% expression), in 33%; p16 loss (<10% expression), in 49%; and at least 1 of these abnormalities, in 92.5%. Cyclin D1 overexpression was associated with poor differentiation (P = 0.027) and signet ring cell type (P = 0.029). pRb expression was lower in lymph node metastases than in the corresponding primary tumors (P <0.001). Univariate and multivariate survival analysis (minimum follow-up 72 months or until death) revealed that <20% pRb expression, <30% pRb expression, and International Union Against Cancer stage >2 were associated with worse overall survival. The results suggest that Rb pathway disturbances play an important role in gastric carcinogenesis. The poor prognosis of cancers with low pRb expression and the reduced pRb expression in lymph node metastases raise the possibility that Rb and related genes also influence progression.
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PMID:Abnormal expression of pRb, p16, and cyclin D1 in gastric adenocarcinoma and its lymph node metastases: relationship with pathological features and survival. 1469 13

Mitogenic growth factor- and integrin-dependent signaling pathways cooperate to control the proliferation of nontransformed cells. As integral mediators of these networks, the Rho family of GTPases play a pivotal role in G1 cell cycle progression, primarily through regulation of cyclin D1 expression, as well as the levels of the cyclin-dependent kinase inhibitors p21cip1 and p27kip1. Such dual control of both the critical positive and negative regulators of G1 progression make the Rho GTPases prime candidates to target the autonomous proliferation which typifies cancer cells. Cyclin D1 has been identified as an important oncogene and the cdk inhibitors as tumor suppressors in human breast carcinogenesis. Evidence pointing to the potential role of Rho-dependent pathways and their interaction with oncogenic Ras in contributing to such cell cycle abnormalities that characterize human breast cancer is also presented.
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PMID:Rho GTPases as key transducers of proliferative signals in g1 cell cycle regulation. 1499 52

It has been shown that a variety of cell cycle-related proteins play important roles in the process of carcinogenesis including hepatocarcinogenesis. In the present study, we evaluated mRNA and protein expression of G1 phase-related cell cycle molecules in the process of hepatocarcinogenesis, using Long-Evans Cinnamon (LEC) rats, an animal model of hepatocellular carcinoma (HCC). The expression of cyclin D1, cyclin-dependent kinase 4 (Cdk4) and Cdk6 was measured quantitatively by real-time polymerase chain reaction. Cyclin D1 mRNA expression was increased significantly in chronic hepatitis liver compared with normal liver, and then decreased in HCC and the surrounding precancerous liver of LEC rats. Levels of Cdk4 mRNA were increased significantly in HCC compared to precancerous and chronic hepatitis livers. In contrast, mRNA levels of Cdk6 did not change significantly during hepatocarcinogenesis. We also evaluated the protein levels of these G1 phase-related cell cycle molecules by Western blot analyses and confirmed similar results. Total amounts of retinoblastoma protein (pRb) in the liver did not change significantly in the process of hepatocarcinogenesis in LEC rats. However, levels of phosphorylated pRb were increased markedly in the process of hepatocarcinogenesis, and the highest in HCC compared to precancerous, chronic hepatitis and normal livers. These results indicate that cyclin D1 may be involved in the regeneration of hepatocytes rather than hepatocarcinogenesis, while Cdk4 but not Cdk6 may play an important role in the development of HCC.
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PMID:Expression of G1 phase-related cell cycle molecules in naturally developing hepatocellular carcinoma of Long-Evans Cinnamon rats. 1506 43

Cyclin D1 is a target molecule transcriptionally activated by aberrant beta-catenin in Wnt signalling, while prolyl isomerase Pin1 promotes cyclin D1 overexpression directly or through accumulation of beta-catenin in cancer cells. This study aimed to elucidate whether Pin1 was involved in cyclin D1 overexpression and aberrant beta-catenin in thyroid tumourigenesis by examining 14 follicular adenomas (FAa) and 14 papillary thyroid carcinomas (PTCs). All PTCs displayed cyclin D1 overexpression and strong cytoplasmic beta-catenin and/or decreased membrane beta-catenin expression by immunohistochemistry. Overexpression of cyclin D1 mRNA was observed in 45.5% of FAs and 54.5% of PTCs by TaqMan real-time PCR. Pin1 expression was observed in PTC by immunostaining and was confirmed by reverse transcriptase-PCR. There was a strong correlation between cyclin D1 and Pin1/cytoplasmic/membrane beta-catenin expression (p < 0.001), and between Pin1 and cytoplasmic (p < 0.001)/membrane (p = 0.002) beta-catenin expression in thyroid tumours. Mutation of the beta-catenin gene could not be detected in PTC. Western blot analysis demonstrated high levels of cyclin D1 and beta-catenin as well as Pin1 expression in a human PTC cell line possessing wild-type beta-catenin and APC genes. This study suggests that both cyclin D1 overexpression and aberrant beta-catenin expression are of significance in thyroid tumours. Pin1 expression appears to correlate closely with the level of cyclin D1 and aberrant beta-catenin expression in thyroid tumours such as FA and PTC. Pin1 may be an important factor in regulating cyclin D1 and beta-catenin expression during thyroid carcinogenesis.
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PMID:Cyclin D1 overexpression in thyroid tumours from a radio-contaminated area and its correlation with Pin1 and aberrant beta-catenin expression. 1509 72

There is little primate risk factor data in the literature evaluating the relationship between proposed mechanisms of PPAR agonist-induced hepatocarcinogenesis at clinically relevant therapeutic exposures. These studies were conducted to characterize the hepatic effects of fenofibrate and ciprofibrate in the cynomolgus monkey. Male cynomolgus monkeys were given fenofibrate (250, 1250 or 2500 mg/kg/day) or ciprofibrate (3, 30, 150 or 400 mg/kg/day) for up to 15 days. The highest doses used were approximately 4 times (fenofibrate) and 9.4 times (ciprofibrate) the human therapeutic exposure for these agents based on AUC (area under the curve). For both compounds, there was a treatment-related increase in liver weight and periportal hepatocellular hypertrophy, which was related to increases in peroxisomes (up to 2.8 times controls) and mitochondria (up to 2.5 times controls). An increase in smooth endoplasmic reticulum probably contributed to the hypertrophy. There was no indication of cell proliferation as determined by the number of mitotic figures and this was confirmed by evaluating cell proliferation by immunohistochemical staining for the Ki-67 antigen. Consistent with the findings by light microscopy, there was no treatment-related effect on the level of mRNA for proteins known to be involved in the control of hepatocyte cell division or apoptosis (e.g. P21, Cyclin D1, PCNA, CDKN1A). Furthermore, there was minimal indication of oxidative stress. Thus, there was no evidence of lipofuscin accumulation, and there was no remarkable increase in the mRNA levels for most proteins known to respond to oxidative stress (e.g. catalase, glutathione peroxidase). A mild induction in the mRNA levels of cellular beta-oxidation and detoxification enzymes (e.g. acyl CoA oxidase, thioredoxin reductase) was observed. Collectively, the data from these studies suggest that the primate responds to PPARalpha agonists in a manner that is different from the rodent suggesting that the primate may be refractory to PPAR-induced hepatocarcinogenesis.
Carcinogenesis 2004 Sep
PMID:Fibrates induce hepatic peroxisome and mitochondrial proliferation without overt evidence of cellular proliferation and oxidative stress in cynomolgus monkeys. 1513 Oct 11

To elucidate carcinogenesis in the endometrium, we investigated cyclin D1 immunoreactivities in 20 normal endometria, 20 endometrial hyperplasias and 141 endometrioid-type endometrial adenocarcinoma. We also evaluated the correlation of cyclin D1 expression with Ki-67, cyclin E, cyclin A, cdk2, p27 and p53, and clinicopathological parameters and prognosis. Cyclin D1 expression increased significantly with histological grade, and the labeling index (LI) for cyclin D1 was 121 +/- 23.4% in G1, 12.7 +/- 23.7% in G2 and 15.7 +/- 18.5% in G3. The LIs were significantly correlated with those for cyclin E, cyclin A and Ki-67, but not with the LIs of cdk2, p27 or p53. In contrast, high cyclin D1 expression was significantly correlated with low p53 expression. Cyclin D1 expression was not significantly correlated with any of the clinicopathological parameters except histological grade. Cyclin D1 expression was significantly correlated with histological grade and proliferative activity, but not clinicopathological parameters and prognosis in endometrial adenocarcinoma.
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PMID:Cyclin D1 expression in endometrioid-type endometrial adenocarcinoma is correlated with histological grade and proliferative activity, but not with prognosis. 1533 Jan 59

Cancer is a genetic disease. Breast cancer tumorigenesis can be described as a multi-step process in which each step is thought to correlate with one or more distinct mutations in major regulatory genes. The question addressed is how far a multi-step progression model for sporadic breast cancer would differ from that for hereditary breast cancer. Hereditary breast cancer is characterized by an inherited susceptibility to breast cancer on basis of an identified germline mutation in one allele of a high penetrance susceptibility gene (such as BRCA1, BRCA2, CHEK 2, TP53 or PTEN). Inactivation of the second allele of these tumour suppressor genes would be an early event in this oncogenic pathway (Knudson's "two-hit" model). Sporadic breast cancers result from a serial stepwise accumulation of acquired and uncorrected mutations in somatic genes, without any germline mutation playing a role. Mutational activation of oncogenes, often coupled with non-mutational inactivation of tumour suppressor genes, is probably an early event in sporadic tumours, followed by more, independent mutations in at least four or five other genes, the chronological order of which is likely less important. Oncogenes that have been reported to play an early role in sporadic breast cancer are MYC, CCND1 (Cyclin D1) and ERBB2 (HER2/neu). In sporadic breast cancer, mutational inactivation of BRCA1/2 is rare, as inactivation requires both gene copies to be mutated or totally deleted. However, non-mutational functional suppression could result from various mechanisms, such as hypermethylation of the BRCA1 promoter or binding of BRCA2 by EMSY. In sporadic breast tumorigenesis, at least three different pathway-specific mechanisms of tumour progression are recognizable, with breast carcinogenesis being different in ductal versus lobular carcinoma, and in well differentiated versus poorly differentiated ductal cancers. Thus, different breast cancer pathways emerge early in the process of carcinogenesis, ultimately leading to clinically different tumour types. As mutations acquired early during tumorigenesis will be present in all later stages, large-scale gene expression profiling using DNA microarray analysis techniques can help to classify breast cancers into clinically relevant subtypes.
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PMID:Oncogenic pathways in hereditary and sporadic breast cancer. 1943 86

Mouse mammary tumor virus (MMTV) has a proven role in breast carcinogenesis in wild mice and genetically susceptible laboratory inbred mice. The carcinogenic characteristics of this virus are enhanced by estrogen and other steroid hormones. MMTV-like envelope gene sequences, with 95% homology to MMTV have been identified in approximately 40% of breast cancers in US, Australian and Argentinian women. The presence of such sequences indicates the presence of a replication competent MMTV-like virus in human breast tumors. Whether an MMTV-like virus contributes to human breast cancer remains to be demonstrated. Non-statistically significant differences in p53 expression between MMTV-like positive and negative human breast cancers have previously been observed. As high p53 protein expression is associated with aggressive breast carcinogenesis we sought to determine if there were associations between the presence of MMTV-like gene sequences and elevated p53 expression in both invasive ductal carcinomas (IDC) and ductal carcinomas in situ (DCIS). We also investigated the expression of other biomarkers which are commonly associated with human breast cancer. These included estrogen receptor, progesterone receptor, Ki67, Cyclin D1, Bcl-2 and HER-2. Using polymerase chain reaction (PCR) analyses, MMTV-like envelope gene sequences were detected in 15 (75%) of 20 IDC specimens and 5 (23%) of 22 DCIS specimens. The average percentage of p53 positive cells in MMTV-like positive IDC specimens was 69% as compared to 44% in MMTV-like negative specimens (p for difference = 0.067). The average percentage of p53 positive cells in MMTV-like positive DCIS specimens was 93% as compared to 35% in MMTV-like negative specimens (numbers too few for statistical analysis). There was an increased intensity of p53 expression in IDC and DCIS specimens that were MMTV-like positive compared to those that were MMTV-like negative. There were no statistically significant differences in age, grade, and percentage of average positive cells for ERa, PR, Ki67, cyclin D1, Bcl-2, and HER-2, between MMTV-like positive and negative breast cancer specimens. Although these observations do not provide evidence of causality, they are consistent with a role for MMTV-like viruses in some human breast cancers.
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PMID:Elevated expression of the tumor suppressing protein p53 is associated with the presence of mouse mammary tumor-like env gene sequences (MMTV-like) in human breast cancer. 1537 46

The NF-kappaB family of transcription factors regulates a wide variety of cellular processes including cell growth, differentiation, and apoptosis. A tissue microarray was constructed from paraffin wax-embedded blocks from 95 endometrial carcinomas (EC), previously studied for microsatellite instability, as well as for alterations in PTEN, k-RAS and beta-catenin. Immunohistochemical evaluation included members of the NF-kappaB (p50, p65, p52, c-Rel, Rel-B) and the IkappaB (IkappaBalpha, IkappaBbeta, IkappaBepsilon, Bcl-3) families, as well as putative targets of NF-kappaB such as Flip, Bcl-xL, Cyclin D1, and oestrogen and progesterone receptors. Results were correlated with the clinical and pathological data. Nuclear immunostaining for members of the NF-kappaB family was frequent in EC (p50, 20%; p65, 16.5-21.9%; p52, 9.3%; c-Rel, 48.9%; Rel-B, 15.7%); and it correlated with negativity for members of the IkappaB family in some cases. There was a statistically significant association between immunoreaction for p50 and p65 (p = 0.006), suggesting activation of the so-called 'classic form' of NF-kappaB, similar to that described in breast cancer. Bcl-3 nuclear immunostaining was detected in 60.7% of cases. The vast majority of p52-positive tumours showed Bcl-3 nuclear immunoreaction (p = 0.038). Immunostaining for putative targets of NF-kappaB was as follows: Bcl-xL, 76.2% (p = 0.001); Flip 43.0%; Cyclin D1, 64.79%. p65 immunostaining correlated with increased immunoreaction for steroid hormone receptors. No correlation was found between NF-kappaB nuclear pattern and the presence of microsatellite instability, or alterations in PTEN, k-RAS, or beta-catenin. These results suggest that the NF-kappaB and IkappaB families of genes may be important in endometrial carcinogenesis, by controlling apoptosis and cell proliferation.
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PMID:Abnormalities in the NF-kappaB family and related proteins in endometrial carcinoma. 1548 Oct 28


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