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)

Cyclin D1 protein plays an important part in regulating the progress of the cell during the G1 phase of the cell cycle. The cyclin D1 gene, CCND1, is amplified in approximately 20% of mammary carcinomas, and the protein is over-expressed in approximately 50% of cases. This has led to intensive study to ascertain whether cyclin D1 is a biological marker in breast cancer; however, the clinical work has produced unexpected results. Work in cell lines and in transgenic mice indicate that CCND1 is a weak oncogene and it was expected that, like c-erbB-2, over-expression of cyclin D1 protein would be associated with a poor prognosis. Early immunohistochemical prognostic studies produced equivocal results but we, and others, have recently shown that strong staining for cyclin D1 is more likely to be seen in well differentiated, estrogen receptor positive carcinomas. Furthermore, we have found that over-expression of cyclin D1 is actually associated with a good outcome, both in terms of prognosis and response to endocrine treatment. Cyclin D1 is frequently over-expressed in ductal carcinoma in situ but not in benign breast disease, including atypical ductal hyperplasia; hence its expression appears to be closely linked with carcinogenesis. In order to help explain the apparent beneficial effects of cyclin D1 over-expression, a number of closely associated cell cycle proteins have also been evaluated, including the cyclin dependent kinase inhibitor p27, which blocks the activating effects of cyclin D1. Initial reports show that high levels of p27 are associated with a good prognosis and we have shown a positive association between p27 and cyclin D1 expression. These clinical results of cyclin D1 are an example of how information obtained from basic cell biology studies needs to be complemented by clinical studies to ascertain the true worth of a prognostic marker.
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PMID:Cyclin D1 in breast cancer. 1006 68

Alterations in cell proliferative activity are a common phenomenon in oral carcinogenesis. In this study, the expression of the cell cycle-associated proteins p16, pRb, p53, p27 and Ki-67 were examined by immunohistochemistry in precancerous and cancerous oral lesions, including verrucous carcinomas (VCs). Generally, expression of pRb, p53 and Ki-67 increased according to the cell proliferative activity or tumor progression, but p27 expression showed an inverse relationship. Comparing squamous cell carcinomas (SCCs) with VCs, there was a great difference in expression levels of p27, Ki-67 and p53, which seemed to reflect the different cell proliferative activities of these two tumors. Expression of p16 was low in both dysplasia and SCCs, whereas p16 expression was high in VCs. The high immunohistochemical expression for both p16 and pRb in VC is quite different compared with SCC, which may indicate a possible relationship between VC and human papillomavirus (HPV) infection.
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PMID:Immunohistochemical analysis of cell cycle-associated proteins p16, pRb, p53, p27 and Ki-67 in oral cancer and precancer with special reference to verrucous carcinomas. 1022 46

The restriction of energy intake has a profound inhibitory effect on carcinogenesis, yet the mechanism or mechanisms that account for this effect are unknown. In this experiment, the hypothesis tested was that energy restriction upregulates the expression of p27/kip1, a gene product associated with cell-cycle growth arrest, while downregulating cyclin D1, a protein that combines with cyclin-dependent kinases to promote phosphorylation of retinoblastoma protein and the progression of cells through the cell cycle. We studied levels of these proteins in uninvolved mammary epithelial cells and in mammary intraductal proliferations, ductal carcinomas in situ, and adenocarcinomas induced in response to administration of 1-methyl-1-nitrosourea in animals fed either ad libitum or 90%, 80%, or 60% of ad libitum intake. Protein levels were evaluated immunohistochemically by using computer-assisted image analysis to quantify differences in protein expression among treatment groups. The expression of p27 increased and the expression of cyclin D1 decreased dose-dependently in response to energy restriction. The effect was greater on p27 than on cyclin D1. The hypothesis proposed is that energy restriction inhibits carcinogenesis by arresting cell-cycle progression by regulating p27/kip1.
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PMID:Effect of energy restriction on the expression of cyclin D1 and p27 during premalignant and malignant stages of chemically induced mammary carcinogenesis. 1032 60

In this report, we describe a novel lytic mechanism exploited by antimicrotubule drugs (AMDs) such as Taxol which are frequently used to treat multiple human cancers including breast and ovarian cancers. In cells lacking the G1-arresting capacity due to the defect in retinoblastoma or p53 gene function, AMDs trigger hyperploid progression and death. The hyperploid progression occurs via continued cell-cycle progression without cell division. Blocking hyperploid progression through hydroxyurea or ectopically expressed p27(Kip1), a G1-specific Cdk inhibitor, abrogates AMD cytotoxicity. Thus, AMDs induce lethality in G1-checkpoint-defective cells by triggering hyperploid progression. The phenomenon is reminiscent of that observed previously with bub-1 yeast mutant. The potential significance of this finding lies in that hyperploid progression-mediated death may be exploited to develop a therapy with tumor-specificity at the genetic level. As a large fraction of human cancers are mutated in p53 gene, it may have a wide therapeutic applicability.
Carcinogenesis 1999 Jul
PMID:Taxol, vincristine or nocodazole induces lethality in G1-checkpoint-defective human astrocytoma U373MG cells by triggering hyperploid progression. 1038 85

In the present study we investigated the expression of the cell cycle inhibitor p27 in endometrial neoplasia using immunohistochemistry with a p27-specific antibody. Expression of p27 in endometrial carcinomas was compared with expression in the normal endometrium throughout the cycle. Normal endometrial cells showed strong nuclear expression of p27. Expression was present throughout the cycle and was stronger during the secretory phase. We found strongly reduced or abolished expression of p27 in endometrial carcinoma (85.3% of cases). The 41 tumours analysed were classified according to p27 staining intensity and percentage of positive cells into the following categories of p27 expression: negative/very low (56.0%); low (29.3%); moderate (14.7%) and high (0.0%). All the p27-positive tumours were well-differentiated endometrioid carcinomas of malignancy grade G1. Comparison with the p53 status showed that all tumours with strong p53 expression had low/negative p27 staining, while those that were positive for p27 had negative/low p53 staining. Reduced or absent p27 levels were also observed by Western blot analysis both in tumour samples and in HEC-1B endometrial adenocarcinoma cells. It thus seems that p27 expression is essential for the control of normal endometrial proliferation, and reduced or absent p27 expression may be an important step in endometrial carcinogenesis.
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PMID:Strongly reduced expression of the cell cycle inhibitor p27 in endometrial neoplasia. 1038 25

p27Kip1 and p21Cip1 are cyclin dependent kinase inhibitors which can arrest cell proliferation and p27 is a tumor suppressor gene. To address the mechanism of tumor suppression by p27 and to determine if p21 has a tumor suppressor phenotype, we utilized the two stage skin carcinogenesis model on p27 and p21 knockout mice. In this model, initiation, which involves mutation of H-ras induced by DMBA, can be distinguished from promotion induced by TPA, and progression to carcinoma. The mean number of papillomas did not differ between p27-/- and control littermates, but papilloma growth rate was increased and carcinomas developed earlier. Thus, p27 deficiency did not enhance initiation, but resulted in more rapid clonal expansion of initiated cells during promotion. TPA treatment reduced p27 expression in keratinocytes also supporting a role for p27 during promotion. Tumors from p27-/- mice contained mutant H-ras indicating that p27 deficiency did not substitute for mutant ras and further, that during ras driven tumor growth, p27 is partially antagonistic since its removal led to faster growth. The treated p27-/- mice also developed intestinal adenomas. p21-/- mice did not display a significant increase in tumor numbers, growth rate or progression to carcinomas and these tumors also had mutated H-ras. Carcinomas from p21-/- mice were more poorly differentiated with a high frequency of anaplastic spindle cell carcinomas. Thus p21 deficiency mainly resulted in higher grade undifferentiated tumors.
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PMID:Tumor suppression by p27Kip1 and p21Cip1 during chemically induced skin carcinogenesis. 1046 16

Tea is a popular beverage. The consumption of green tea is associated with a lower risk of several types of cancer, including stomach, esophagus, and lung. The cancer chemopreventive effect of tea has been attributed to its major phytopolyphenols. The tea polyphenols comprise about one-third of the weight of the dried leaf, and they show profound biochemical and pharmacological activities including antioxidant activities, modulation of carcinogen metabolism, inhibition of cell proliferation, induction of cell apoptosis, and cell cycle arrest. They intervene in the biochemical and molecular processes of multistep carcinogenesis, comprising tumor initiation, promotion, and progression. Several studies demonstrate that most tea polyphenols exert their scavenging effects against reactive oxygen species (ROS); excessive production of ROS has been implicated for the development of cardiovascular diseases, neurodegenerative disorders, and cancer. Recently, we have found that the major tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) suppresses extracellular signals and cell proliferation through epidermal growth factor receptor binding in human A431 epidermoid carcinoma cells; EGCG also blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of the transcription factor NFKB in macrophages. Furthermore, EGCG blocks the cell cycle at the G1 phase in MCF-7 cells. We have demonstrated that EGCG inhibits the activities of cyclin-dependent kinases 2 and 4; meanwhile, EGCG induces the expression of the Cdk inhibitors p21 and p27. These results suggest that tumor promotion can be enhanced by ROS and oxidative mitotic signal transduction, and this enhancement can be suppressed by EGCG or other tea polyphenols.
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PMID:Cancer chemoprevention by tea polyphenols through mitotic signal transduction blockade. 1050 43

The p27(Kip1) protein is a negative regulator of the cell cycle and a potential tumor suppressor gene. Reduced expression of the p27(Kip1) protein has been reported in several human tumors and has been associated with higher tumor grade and increased mortality in breast, lung, colon, prostate, bladder, and gastric cancers. On the other hand, increased expression of the p27(Kip1) protein, in the absence of gene mutation, has been observed in primary colon and breast cancers. It was recently suggested that sequestration in the cytoplasm might be an alternative way to inactivate p27(Kip1)-associated inhibitory activity. This study was undertaken to further evaluate p27(Kip1) expression in primary colon tumors and to verify whether differences exist between normal and cancer tissues in terms of subcellular localization of this protein. Both normal and neoplastic tissues expressed variable amounts of the p27(Kip1) protein, as assessed by western blot analyses. Although the mean values were not different between tumor and normal mucosa samples, the expression of total p27(Kip1) was reduced in a subset of tumors. Decreased levels of total p27(Kip1) were associated with high tumor grade (P=0.03) and stage (P=0.04). Moreover, while there was no significant difference in nuclear p27(Kip1), the amount of p27(Kip1) in the cytoplasmic fraction was significantly higher in the tumor samples than in the normal mucosa samples (P=0.0001). These results suggest that p27(Kip1) expression is lost in a subset of colorectal tumors and that alterations in the subcellular localization of this protein might play a role in colon carcinogenesis.
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PMID:Reduced expression and altered subcellular localization of the cyclin-dependent kinase inhibitor p27(Kip1) in human colon cancer. 1055 92

Proliferation in the setting of longstanding chronic inflammation appears to predispose to carcinoma in the liver, large bowel, urinary bladder, and gastric mucosa. Focal prostatic atrophy, which is associated with chronic inflammation, is highly proliferative (Ruska et al, Am J Surg Pathol 1998, 22:1073-1077); thus the focus of this study was to more fully characterize the phenotype of the atrophic cells to assess the feasibility of the proposal that they may be targets of neoplastic transformation. The pi-class glutathione S-transferase (GSTP1), a carcinogen-detoxifying enzyme, is not expressed in >90% of prostate carcinomas (CaPs). GSTP1 promoter hypermethylation, which appears to permanently silence transcription, is the most frequently detected genomic alteration in CaP (Lee et al, Proc Natl Acad Sci USA 1994, 91:11733-11737; >90% of cases). In high-grade prostatic intraepithelial neoplasia (PIN), this alteration is present in at least 70% of cases (Brooks et al, Cancer Epidemiol Biomarkers Prev, 1998, 7:531-536). Although normal-appearing prostate secretory cells rarely express GSTP1, they remain capable of expression, inasmuch as GSTP1 promoter hypermethylation is not detected in normal prostate. Fifty-five lesions from paraffin-embedded prostatectomy specimens (n = 42) were stained for GSTP1, using immunohistochemistry. Adjacent sections were stained for p27(Kip1), Ki-67, androgen receptor (AR), prostate-specific antigen (PSA), prostate-specific acid phosphatase (PSAP), Bcl-2, and basal cell-specific cytokeratins (34betaE12). With normal prostate epithelium as the internal standard, staining was scored for each marker in the atrophic epithelium. The lesions showed two cell types, basal cells staining positive for 34betaE12, and atrophic secretory-type cells staining weakly negative for 34betaE12. All lesions showed elevated levels of Bcl-2 in many of the secretory-type cells. All lesions had an elevated staining index for the proliferation marker Ki-67 in the secretory layer and decreased expression of p27(Kip1), a finding reminiscent of high-grade PIN (De Marzo et al, Am J Pathol 1998, 153:911-919). Consistent with partial secretory cell differentiation, the luminal cells showed weak to moderate staining for androgen receptor and the secretory proteins PSA and PSAP. All atrophic lesions showed elevated GSTP1 expression in many of the luminal secretory-type cells. Because all lesions are hyperproliferative, are associated with inflammation, and have the distinct morphological appearance recognized as prostatic atrophy, we suggest the term "proliferative inflammatory atrophy" (PIA). Elevated levels of GSTP1 may reflect its inducible nature in secretory cells, possibly in response to increased electrophile or oxidant stress. Elevated Bcl-2 expression may be responsible for the very low apoptotic rate in PIA and is consistent with the conclusion that PIA is a regenerative lesion. We discuss our proposal to integrate the atrophy and high-grade PIN hypotheses of prostate carcinogenesis by suggesting that atrophy may give rise to carcinoma either directly, as previously postulated, or indirectly by first developing into high-grade PIN.
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PMID:Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. 2017 14

Alteration in cell cycle regulators is considered to play an important role in carcinogenesis. In order to cast light on changes in reversible hyperplastic and irreversible tumorigenic lesions in the rat urinary bladder, expression of p27(Kip1), cyclin D1 and cyclin E proteins was sequentially compared. In the first study, 3% uracil was fed for 4 weeks to cause urinary calculi and consequent hyperplasia and papillomatosis, both regressing after withdrawal of the insult. Compared with normal bladder epithelium, in papillomatosis at week 4, the BrdU index and immunohistochemical positivities for cyclin D1 and cyclin E were significantly elevated, whereas values for p27(Kip1) tended to be reduced. One week after withdrawal of uracil, the BrdU index and positivities for cyclin D1 and cyclin E were decreased to below the control levels, while positivity for p27(Kip1) was dramatically increased, with a strong staining intensity. In a second study, rats were initiated with a bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine for 4 weeks, then fed 3% uracil for 8 weeks. During this latter period, expression of cyclin D1, cyclin E and p27(Kip1) in hyperplastic urothelium were comparable with those in the first study. One week after withdrawal of uracil, most urothelial lesions regressed, showing high p27(Kip1) and low cyclin D1 and cyclin E staining. Two weeks after uracil withdrawal, transitional cell carcinomas, with a low p27(Kip1) and high cyclin D1 and cyclin E staining pattern, could be easily distinguished from surrounding regressing epithelium. These data indicate that during regression of papillomatosis after cessation of a proliferative stimulus, expression of p27(Kip1)is elevated, accompanied by a lowering of cyclin D1 and cyclin E. In irreversible tumorous bladder lesions, on the other hand, persistent low expression of p27(Kip1) and elevated cyclin D1 and cyclin E are characteristic.
Carcinogenesis 2000 Jan
PMID:Aberrant expression of p27(Kip1) is associated with malignant transformation of the rat urinary bladder epithelium. 1060 43


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