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)

In the course of our study on the amplification of 11q13 sequences in human breast cancer, we have investigated the amplification status of the anonymous DNA fragment D11S97 in a series of 125 mammary tumors. Our results indicate that, as with bladder carcinomas, D11S97 can be amplified separately from BCL1. In addition, we have shown that D11597 is physically linked to both D11S146 and BCL1, and is less than 100 kb centromeric to the D115146. These results indicate that, in addition to other 11q13 loci, sequences located approximately 500 kb centromeric from BCL1 could contribute to carcinogenesis of epithelial cells in vivo.
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PMID:Amplification of 11q13 DNA sequences in human breast cancer: D11S97 identifies a region tightly linked to BCL1 which can be amplified separately. 156 70

Changes which lead to excessive cyclin production or to loss of cell cycle inhibition by proteins such as p16/MTS1 may release breast tumour cells from the constraints of cell division. In order to establish the frequency of MTS1/p16 gene alteration and its relation with genetic damage to the p53 and cyclin D1 genes, we have studied these gene abnormalities in 164 human primary breast cancers and in six breast cancer cell lines. Two breast cancer cell lines and one primary tumour showed a homozygous deletion of exon 2 of the MTS1 gene. Using single-strand conformation polymorphism and subsequent sequencing analysis, one tumour showed an alteration at codon 67 (CCC-->CTC; Pro to Leu). Another tumour showed a mutation at codon 98 (without amino acid change) with an additional polymorphism at codon 140. This polymorphism was also found in 13 other tumour samples, but has no effect on (disease-free) survival. From these data we conclude that the occurrence of CDKN2 (p16/MTS1) mutation in primary breast cancer is a rare event and is not likely to be involved in human breast tumour carcinogenesis and progression.
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PMID:Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer. 754 49

Dysregulation of cyclin expression has been reported for several human malignancies, including breast cancer. To further investigate the role of cyclin genes in mammary tumorigenesis we analyzed the expression of cyclins D1, E and A and other cell cycle-related proteins in a series of nine N-methyl-N-nitrosourea-induced primary rat mammary tumors. Western blot analysis revealed a 10- to 15-fold increase in the level of cyclin D1 protein in most (7/9) of the tumors, when compared with normal rat mammary gland. The two tumors that did not show this increase also displayed negligible levels of the retinoblastoma protein. A moderate increase, 1.5- to 2-fold, in the level of cyclin E was observed in four tumors and three tumors displayed abnormal low molecular weight cyclin E-related proteins. None of the tumors showed amplification of the cyclin D1 or E genes when studied by Southern blot analysis. All nine tumors showed a 2- to 6-fold increase in the level of cyclin A protein. Most of the tumors also displayed a marked increase in levels of the CDK2 and CDK4 proteins. These changes did not appear to be simply a consequence of increased cell proliferation, as assessed by proliferating cell nuclear antigen analysis. Thus, aberrant expression of cyclins and other cyclin-related genes occurs frequently in mammary tumorigenesis in both rodents and humans.
Carcinogenesis 1995 Sep
PMID:Deregulated expression of cyclin D1 and other cell cycle-related genes in carcinogen-induced rat mammary tumors. 755 74

Since PKC epsilon functions as an oncogene when stably overexpressed in R6 rat fibroblasts (Cacace et al. 1993) in the present study we examined whether transformed R6-PKC epsilon cells display abnormalities in the expression of specific early response and cyclin genes. When vector control and R6-PKC epsilon cells were starved of serum for 72 h they arrested in G0/G1 and showed passage through the cell cycle at similar rates after subsequent stimulation with 10% fetal calf serum plus TPA. In PKC epsilon cells, induction of cyclin D1 protein was markedly reduced, and that of cyclin A was slightly reduced when compared to control cells. Northern blot analyses indicated that decreased expression of cyclin D1 and A protein in PKC epsilon cells is due to translational or post-translational effects. A study of early response gene expression in PKC epsilon cells indicated that there was a marked reduction in the expression of c-fos mRNA but not in c-jun or c-myc mRNAs. The marked decreases in cyclin D1 and c-fos expression seen in PKC epsilon cells were not seen in R6 cells that overexpress PKCs alpha or beta. These findings suggest that PKC epsilon cells bypass certain normal signal transduction and cyclin-controlled pathways involved in cell proliferation.
Carcinogenesis 1995 Oct
PMID:Altered expression of cyclins and c-fos in R6 cells that overproduce PKC epsilon. 758 46

Deregulated expression of G1 cyclins D1 and D2 is a feature of some neoplasias. This study examined the altered expression of D1 and D2 cyclins, both the total pool and as associated with cdk4 and cdk2, at different stages of mouse mammary tumorigenesis. Three different mammary hyperplastic outgrowth lines, TM2, TM10 and TM12, and their respective tumors were examined. Increasing levels of the cyclin D1 protein pool, D1 binding to cdk4 and cdk2 and cdk4 kinase activity were closely correlated with tumorigenesis. In constrast, cyclin D2 binding to cdk4 was predominant in hyperplasias and much less in tumors, where cyclin D1 became predominant. However, the cyclin D2 pool showed increases of 15-65 times in hyperplasias compared with normal gland and further increases of 11-15 times in two of three different tumors. The message level for cyclin D1 increased only 2-3 times in tumors compared with normal gland. Cyclin D2 mRNA was highest in normal tissue and decreased only marginally in tumors. These results suggest that cyclin D2 functions uniquely from cyclin D1 in the early stages of mouse mammary tumor development. Cyclin D2 bound to cdk4 may act to guarantee a low level of kinase activity in hyperplasias and may be an attempt to direct the mammary epithelial cells through differentiation rather than proliferation. This interaction may be one of the negative regulatory mechanisms in the early stages in mouse mammary tumor development, until cyclin D1 totally replaces cyclin D2 binding to cdk4, which would activate the high levels of cdk4 kinase activity observed in neoplasias.
Carcinogenesis 1995 Oct
PMID:Mouse mammary hyperplasias and neoplasias exhibit different patterns of cyclins D1 and D2 binding to cdk4. 758 59

Deregulated expression of transforming growth factor alpha (TGF-alpha) or c-myc has been implicated in the genesis of human breast cancer. To better characterize the role of these molecules in this disease, we generated transgenic mice that express TGF-alpha or c-myc under control of the mouse whey acidic protein (WAP) promoter. We then compared the resulting mammary gland neoplasia in these mice and in previously described mice expressing a metallothionein-driven TGF-alpha transgene. Nonvirgin female mice in all transgenic lineages developed mammary tumors with 100% incidence but variable latency. Among TGF-alpha lines, mean survival time correlated with the level of transgene expression, and the average life spans of high-expressing WAP-TGF-alpha and WAP-c-myc mice were similarly reduced. The majority of TGF-alpha-induced tumors were relatively well-differentiated adenomas and adenocarcinomas; in contrast, WAP-c-myc tumors were poorly differentiated, solid carcinomas with a minority of adenocarcinomas. Most TGF-alpha and all c-myc-induced tumors were transplantable, but lung metastases were infrequently observed in all transgenic lines. WAP-TGF-alpha-induced tumors, in marked contrast to those induced by WAP-c-myc, displayed frequent induction of cyclin D1 mRNA, suggesting that expression of this gene may complement that of TGF-alpha during mammary tumor development. Expression of TGF-alpha also induced precocious development of pregnant glands and delayed or inhibited mammary involution. As a result, multiparious MT-TGF-alpha and especially WAP-TGF-alpha females accumulated large numbers of hyperplastic alveolar nodules that resembled the more differentiated TGF-alpha-induced tumors. Finally, coexpression of WAP-c-myc and WAP-TGF-alpha transgenes markedly decreased tumor latency, increased tumor growth, and even induced mammary tumors in virgin female and male mice. These findings provide further evidence for the importance of deregulated TGF-alpha expression in multistage carcinogenesis, and they suggest that in the mammary gland the mechanism of TGF-alpha-induced transformation may depend on postlactational survival of differentiated epithelium. They also provide evidence of a potent tumorigenic collaboration between TGF-alpha and c-myc in mammary epithelium.
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PMID:Inhibition of mammary gland involution is associated with transforming growth factor alpha but not c-myc-induced tumorigenesis in transgenic mice. 764 Dec 11

Abnormal expression of cell-cycle regulatory proteins, particularly cyclin D1, has been described in human cancers. However, there are few reports of this kind in experimental carcinogenesis models, which provide a framework to analyze the importance of those alterations in early cancer development. Previous studies from our laboratory showed that cyclin D1 mRNA was overexpressed in skin tumors generated in SENCAR mice by a two-stage carcinogenesis protocol. In the study presented here, immunoprecipitation of fresh tumor samples confirmed the overexpression of cyclin D1 protein. We also developed an immunohistochemical technique to determine which cells in the lesions overexpressed the cyclin and the timing of deregulation during cancer development. Surprisingly, we found that all premalignant lesions, including small incipient papillomas, overexpressed cyclin D1, whereas normal and hyperproliferative skin were negative. Nuclear immunostaining was detected only in the proliferative compartments of the tumors and showed an apparent cell-cycle-related variation. These results provide evidence for a role of cyclin D1 overexpression in mouse skin carcinogenesis and support the use of this model as an alternative to in vitro studies to help understand the involvement of cyclin deregulation in cancer development.
Carcinogenesis 1995 Apr
PMID:Early overexpression of cyclin D1 protein in mouse skin carcinogenesis. 772 55

We examined the expression of cyclin D1 mRNA in two human carcinoma cell lines (A431 and TT) and 17 specimens of esophageal cancer with in situ hybridization. Cyclin D1 mRNA was overexpressed in the cytoplasm of cancer cells that showed cyclin D1 gene amplification by Southern blot hybridization. Cyclin D1 antigen was overexpressed in the nucleus of these cancer cells. The distribution of cyclin D1 mRNA-positive cells was similar to that of cyclin D1 antigen-positive cells in the cancer tissues. We then attempted to correlate overexpression of cyclin D1 antigen and prognosis, by using 55 formalin-fixed, paraffin-embedded specimens of esophageal cancer. The overall 5-year survival of patients with strongly staining tumors was significantly lower than that of patients with weakly or nonstaining tumors (7 versus 59%; P < 0.01). There was no significant correlation between cyclin D1 expression and other clinicopathological factors. These results suggest that cyclin D1 may play an important role in carcinogenesis and that cyclin D1 overexpression may be a useful prognostic factor in esophageal cancer.
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PMID:Overexpression and localization of cyclin D1 mRNA and antigen in esophageal cancer. 774 10

50C10 and 52H10 are two DNA clones previously reported by us to be overexpressed in human colonic mucosa at high risk for development of colonic tumors. This report presents sequencing data that reveal that these clones contain repetitive Alu elements. Each Alu sequence is associated with a 3'-oligoadenylate [oligo(A)] sequence, which is demonstrated to exhibit instability in human colonic tumors. The oligo(A) sequences only decrease in length, unlike microsatellites, which can either increase or decrease. Rigorous quantitative analysis of the length of the oligo(A) sequence in colonic tumors demonstrates that the standard deviation of the length of the sequence in tumors is a function of the mean length; i.e., as the oligo(A) sequence becomes progressively shorter, the variance increases. Both measurements, therefore, provide a quantitative index of the extent of instability in a tissue. Comparison of instability at the oligo(A) loci defined by 50C10 and 52H10 to instability at a CA microsatellite upstream of the apoD gene, and comparison of an oligo(A) and a CA microsatellite both in the 3' untranslated region of the cyclin D1 mRNA demonstrate that instability in a tumor, when present, is more prominent for the oligo(A) sequences than for the microsatellite (P < 0.0001). This suggests either that the mechanisms that generate oligo(A) instability are more penetrant than those that generate microsatellite instability, or that the instability at oligo(A) sequences takes place earlier in the development of the tumor and is selected for, thus becoming more prominent. These features of oligo(A) instability suggest that they may be uniquely useful in detecting and quantifying instability in tissues. Further, the presence of repetitive sequence elements in loci overexpressed in colonic mucosa at risk may be related to an extensive literature that demonstrates that a variety of repetitive sequences accumulate in the cellular RNA population during carcinogenesis and in tumors. Such RNA sequences could play a mechanistic role in tumor development.
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PMID:Presence and instability of repetitive elements in sequences the altered expression of which characterizes risk for colonic cancer. 780 30

The objective of this study was to quantify the changes in p53 and cyclin D1 protein levels in different stages of human esophageal and gastric cardia carcinogenesis in a high-risk population in Henan, China. Immunoreactivity of p53, cyclin D1 and proliferating-cell nuclear antigen (PCNA) was observed in the cell nuclei of esophageal and gastric cardia biopsies. The number of p53-immunostaining-positive cells was low in normal epithelia, slightly increased in basal-cell hyperplasia (BCH), markedly increased in dysplasia (DYS) (10-fold), and further increased in squamous-cell carcinoma (SCC) (40-fold). This pattern of change was similar to that of cell proliferation as indicated by PCNA immunostaining. On the other hand, the number of cyclin D1-immunostaining-positive cells did not increase from BCH to DYS, although a slight increase from DYS to SCC was noted. In the gastric cardia, again, the pattern of change of p53-positive cells in different stages of lesions paralleled the pattern of cell proliferation. The number of p53-positive cells was very low, much lower than that of PCNA-positive cells, in normal, chronic superficial gastritis (CSG) and chronic atrophic gastritis (CAG); therefore, the increase of p53-positive cells from CAG to DYS was more dramatic (100-fold). From DYS to adenocarcinoma (AC), the p53-positive and the PCNA-positive cells increased 4-fold. On the other hand, the number of cyclin D1-positive cells did not increase in pre-cancerous lesions, but increased slightly in AC. This study demonstrates that p53 protein accumulation increased with the progression of pre-cancerous lesions, especially in the genesis of dysplasia, both in the esophagus and in the gastric cardia. Our approach of quantitative immunohistochemistry sheds light on the mechanisms of genesis of esophageal and gastric-cardia cancers, which frequently occur together in many high-incidence areas.
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PMID:Changes in p53 and cyclin D1 protein levels and cell proliferation in different stages of human esophageal and gastric-cardia carcinogenesis. 796 Feb 22


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