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)

Recent studies have revealed significant efficacy of the marine sponge glycolipid, alpha-galactosylceramide (alpha-GalCer), in treatment of experimental metastatic cancers, infections, and autoimmune diseases. However, the capacity of alpha-GalCer to prevent tumor development had never, to our knowledge, been evaluated in mouse models of chemical- and oncogene-dependent carcinogenesis. In this study, we demonstrate that long-term administration of soluble alpha-GalCer, spanning the time of tumor initiation, inhibits primary tumor formation in three different models: methylcholanthrene-induced sarcomas, mammary carcinomas in Her-2/neu transgenic mice, and spontaneous sarcomas in p53-/- mice. Weekly treatment of mice with alpha-GalCer maintained lymphoid tissue natural killer cell and T cell activation and elevated serum IFN-gamma and IL-4 concentrations. Consistent with the antimetastatic activity of alpha-GalCer, prevention of methylcholanthrene-induced sarcoma was IFN-gammaand tumor necrosis factor-related apoptosis-inducing ligand dependent, but not perforin-dependent. Taken together, our results demonstrate that NK1.1+alphabetaTCR+ cell-based immune therapy can inhibit primary tumorigenesis.
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PMID:Alpha-galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis. 1286 93

In this study we have investigated the influence of dietary mono- and polyunsaturated lipids on 7,12-dimethylbenz(alpha)anthracene (DMBA)-induced mammary tumorigenesis, and the modulation of expression of c-erbB1/EGFR and c-erbB2/neu as a mechanism of this influence. Two series of Sprague-Dawley rats were given a single dose of DMBA. Animals from Series 1 were fed a semi-synthetic low-fat or high-fat corn oil diet, following an initiation-promotion experimental design. Rats from Series 2 were fed low-fat or different high-fat diets (rich in corn oil or rich in olive oil) in the promotion stage of mammary carcinogenesis. High corn oil diet showed clearly a stimulatory effect on experimental breast carcinogenesis, suggesting a role of this kind of lipids on initiation and promotion of mammary tumorigenesis. Moreover, results suggested that olive oil acts as a negative modulator of the experimental breast cancer. On the other hand, two transcripts of EGFR and one neu mRNA were detected by chemiluminescent Northern blot in mammary adenocarcinomas. Analysis of data showed the tendency that high-fat corn oil diet decreases the 2.7 kb mRNA of EGFR, encoding a truncated form of the receptor with no enzimatic activity. High-fat olive oil diet increased EGFR mRNA levels, specially those from 2.7 kb, and decreased the relative abundance of neu mRNA. These data suggest that the modulating effect of dietary lipids on mammary carcinogenesis could result in changes of EGFR and neu mRNA, leading to an increase of EGFR activity by high-fat corn oil diet and a decrease of EGFR and Neu signal transduction pathway by high-fat olive oil diet.
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PMID:Modulation of EGFR and neu expression by n-6 and n-9 high-fat diets in experimental mammary adenocarcinomas. 1288 17

Alterations of the HER-2 (erbB-2/neu) proto-oncogene have been associated with carcinogenesis and poor prognosis of certain cancers. A single nucleotide polymorphism (Ile/Val, A/G) in the transmembrane domain was reported to be associated with a risk of breast cancer. In our study, we examined the association between the HER-2 polymorphism and gastric carcinoma. The Ile/Ile, Ile/Val and Val/Val genotypes were found in 146 (68.9%), 56 (26.4%) and 10 (4.7%) of 212 gastric cancer patients and in 234 (81.5%), 48 (16.7%) and 5 (1.8%) of 287 control subjects, respectively. The Ile/Val or Val/Val genotype was significantly more frequent in patients than in controls (p = 0.005 and 0.033, respectively). The OR of Val/Val genotype then revealed a significantly enhanced risk of 3.25 (95% CI 1.09-9.70) compared to Ile/Ile genotype; heterozygous Ile/Val genotype showed an intermediate risk of 1.97 (1.27-3.06). In patients, carcinomas of advanced stage were significantly more frequent in patients with Ile/Val or Val/Val genotype than those with Ile/Ile genotype (p < 0.001). The logistic regression analysis for tumor invasion, lymph node metastasis and distant metastasis revealed that lymph node metastasis was most closely associated with the HER-2 genotype. These results suggest that this nucleotide polymorphism in the transmembrane domain-coding region of HER-2 could be associated with development of gastric carcinoma and may serve as a predictor of risk for a malignant phenotype of gastric cancer. The association of HER-2 genotype with clinicopathologic characteristics of gastric cancer was also suggested, which has to be confirmed with a larger sample size.
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PMID:A single nucleotide polymorphism in the transmembrane domain coding region of HER-2 is associated with development and malignant phenotype of gastric cancer. 1452 Jun 97

Regarding HER-2/neu expression (gene or protein level) in lung cancer, several studies with inconsistent results have been recently reported, partially due to variable techniques used and/or heterogeneous populations examined. The objective of this study was to examine HER-2/neu expression in a well-defined cohort of non-small-cell lung cancers (NSCLC) and in nonneoplastic lung tissue utilizing a combination of high-density tissue microarray, immunohistochemistry (IHC), and fluorescent in situ hybridization (FISH) under uniform test conditions. One hundred forty stage I-IIIA primary NSCLCs and 38 non-neoplastic lung samples were examined. IHC, using an FDA-approved Hercept monoclonal antibody kit, was performed and HER-2/neu gene alteration was assessed by FISH. The association of expression of HER-2/neu with clinicopathologic parameters was analyzed. Ninety-four percent of tumor samples (131/140) were fully interpretable after tissue processing. Twenty-five of them (19%) overexpressed (2+, 3+) HER-2/neu, while 106 (81%) had no or weak expression. All thirty-four interpretable non-neoplastic lung samples were negative for HER-2/neu alteration at protein and gene level. HER-2/neu protein overexpression correlated well with HER-2/neu gene amplification (r =.83, P < 0.001). HER-2/neu overexpression was significantly associated with histologic subtype: 19 adenocarcinomas (19/82, 23%) versus 4 squamous cell carcinomas (4/44, 9%) overexpressed Her-2/neu (P = 0.04). Statistical significance was observed between HER-2/neu expression and tumor differentiation, with strong positive (3+) expression observed more frequently in poorly differentiated tumors (P = 0.01). Patients with HER-2/neu abnormalities, particularly HER-2/neu gene amplification, exhibited a shorter survival (P = 0.043). The statistically significant difference (P < 0.005) between HER-2/neu alteration in tumor samples(25/131, 19%) and in the nonneoplastic tissue (0/34, 0%) implies that HER-2/neu may have a role in the carcinogenesis of NSCLC. The findings provide evidence supporting the hypothesis that the HER-2/neu receptor may represent a useful molecular target in the treatment of NSCLC. The significant association of HER-2/neu expression and gene amplification with poorly differentiated carcinoma compared with well differentiated carcinoma suggests that HER-2/neu may be involved in NSCLC tumor evolution. Patients with HER-2/neu gene amplification and strong positive expression of HER-2/neu protein showed a strong tendency toward shorter survival.
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PMID:HER-2/neu protein expression and gene alteration in stage I-IIIA non-small-cell lung cancer: a study of 140 cases using a combination of high throughput tissue microarray, immunohistochemistry, and fluorescent in situ hybridization. 1463 6

Modulation of tumor suppressor activities may provide new opportunities for cancer therapy. Here we show that disruption of the gene Ppm1d encoding Wip1 phosphatase activated the p53 and p16 (also called Ink4a)-p19 (also called ARF) pathways through p38 MAPK signaling and suppressed in vitro transformation of mouse embryo fibroblasts (MEFs) by oncogenes. Disruption of the gene Cdkn2a (encoding p16 and p19), but not of Trp53 (encoding p53), reconstituted cell transformation in Ppm1d-null MEFs. In vivo, deletion of Ppm1d in mice bearing mouse mammary tumor virus (MMTV) promoter-driven oncogenes Erbb2 (also called c-neu) or Hras1 impaired mammary carcinogenesis, whereas reduced expression of p16 and p19 by methylation-induced silencing or inactivation of p38 MAPK correlated with tumor appearance. We conclude that inactivation or depletion of the Wip1 phosphatase with resultant p38 MAPK activation suppresses tumor appearance by modulating the Cdkn2a tumor-suppressor locus.
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PMID:Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. 1505 81

A vaccine combining IL-12 and allogeneic mammary carcinoma cells expressing p185(neu) completely prevents tumor onset in HER-2/neu transgenic BALB/c mice (NeuT mice). The immune protection elicited was independent from CTL activity. We now formally prove that tumor prevention is mainly based on the production of anti-p185(neu) Abs. In the present studies, NeuT mice were crossed with knockout mice lacking IFN-gamma production (IFN-gamma(-/-)) or with B cell-deficient mice (microMT). Vaccination did not protect NeuT-IFN-gamma(-/-) mice, thus confirming a central role of IFN-gamma. The block of Ab production in NeuT-microMT mice was incomplete. About one third of NeuT-microMT mice failed to produce Abs and displayed a rapid tumor onset. By contrast, those NeuT-microMT mice that responded to the vaccine with a robust production of anti-p185(neu) Ab displayed a markedly delayed tumor onset. In these NeuT-microMT mice, the vaccine induced a lower level of IgG2a and IgG3 and a higher level of IgG2b than in NeuT mice. Moreover, NeuT-microMT mice failed to produce anti-MHC class I Abs in response to allogeneic H-2(q) molecules present in the cell vaccine. These findings show that inhibition of HER-2/neu carcinogenesis depends on cytokines and specific Abs, and that a highly effective vaccine can rescue Ab production even in B cell-deficient mice.
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PMID:Immunoprevention of mammary carcinoma in HER-2/neu transgenic mice is IFN-gamma and B cell dependent. 1529 41

Pediatric neurogenic tumors include primitive neuroectodermal tumors (PNETs), especially medulloblastoma; ependymomas and choroid plexus papillomas; astrocytomas; retinoblastoma; and sympathetic neuroblastoma. Meningiomas and nerve sheath tumors, although uncommon in childhood, are also significant because they can result from exposures of children to ionizing radiation. Specific chromosomal loci and specific genes are related to each of these tumor types. Virtually all these genes appear to act as tumor suppressor genes, which are inactivated in tumor cells by mutations or by chromosomal loss. In genetically engineered mice, some genes that are clearly associated with specific human tumors (e.g., RB1 in retinoblastoma and NF2 in meningiomas and schwannomas) have no such effect. Other genetic constructs in mice involving the genes p53, ptc1, and Nf1 have produced tumors remarkably similar to some of the human pediatric neoplasms. Some of these tumors become clinically apparent after only a few weeks, while the mice are still juveniles, especially when two or more tumor suppressor genes are inactivated in the same genetic construct. Conversely, at least one genetic pathway in rodents involving point mutation in the coding region of a transforming gene (neu in malignant schwannomas) does not appear to operate in any human tumors. The nervous system is markedly susceptible to experimental carcinogenesis during early life in rodents, dogs, primates, and other nonhuman species, and there is no obvious reason why this generalization should not also apply to humans. However, except for therapeutic ionizing radiation, no physical, chemical, or biological cause of human pediatric nervous system tumors is known. The failure of experimental transplacental carcinogenesis to mirror human pediatric experience more closely may reflect the need for multiple mutational events in target cells, and for experimental carcinogens that are capable of causing the full spectrum of mutations that occur in cancer-related genes in pediatric neurogenic tumors.
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PMID:Causation of nervous system tumors in children: insights from traditional and genetically engineered animal models. 1531 89

The vitamin D(3) receptor (VDR) is a ligand-dependent transcription factor implicated in regulation of cell cycle, differentiation and apoptosis of both normal and transformed cells derived from mammary gland. In these studies we examined whether VDR status altered mammary gland morphology or transformation in the well-characterized MMTV-neu transgenic model of breast cancer. We demonstrate that VDR protein is highly expressed in neu-positive epithelial cells of preneoplastic lesions, established tumors and lung metastases from MMTV-neu mice. Furthermore, MMTV-neu mice lacking VDR exhibit abnormal mammary ductal morphology characterized by dilated, distended ducts containing dysplastic epithelial cells. From 12 months of age on, MMTV-neu mice lacking VDR also experience body weight loss, atrophy of the mammary fat pad, estrogen deficiency and reduced survival. The limited survival of MMTV-neu mice lacking VDR precluded an accurate assessment of the impact of complete VDR ablation on tumor development. MMTV-neu mice heterozygous for VDR, however, did not exhibit body weight loss, mammary gland atrophy or compromised survival. Compared with MMTV-neu mice with two copies of the VDR gene, haploinsufficiency of VDR shortened the latency and increased the incidence of mammary tumor formation. Tumor histology and expression/subcellular localization of the neu transgene were not altered by VDR haploinsufficiency despite a significant decrease in tumor VDR expression. Collectively, these studies suggest that VDR gene dosage impacts on age-related changes in ductal morphology and oncogene-induced tumorigenesis of the mammary gland in vivo.
Carcinogenesis 2004 Dec
PMID:Vitamin D receptor status alters mammary gland morphology and tumorigenesis in MMTV-neu mice. 1533 67

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

Development of the mammary gland is controlled by hormones and many other growth factors. Hyperplasia and neoplasia are thus a likely consequence of alterations in their number and type, or the number and function of their receptors. p185neu, a member of the epidermal growth factor family, is coded by the ErbB-2 oncogene. It is expressed in the normal human breast, but overexpressed and associated with a poor prognosis in 15-30% of breast tumours. Employment of ErbB-2 sequences as vaccinal antigens to induce an immune rejection of such tumours is being investigated in several transgenic animal models. One of the most aggressive models of mammary p185neu-dependent carcinogenesis is that of BALB-neuT mice, which are transgenic for the rat transforming Her-2/neu oncogene (a homologue of the human ErbB-2 oncogene). The progression of their early neoplastic lesions can be prevented with both cellular and DNA vaccines coadjuvated by antiangiogenic and immunostimulatory molecules. This suggests that induction of a specific immune reaction against a tumor target antigen may provide a way of preventing the onset of tumours in subjects with a high genetic risk of developing cancer.
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PMID:Immunobiology of her-2/neu transgenic mice. 1568 5


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