Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have documented mortality and cancer incidence in the families of 67 patients with ataxia-telangiectasia and 48 patients with xeroderma pigmentosum resident in Britain. For both diseases, parents of patients are obligate heterozygotes and grandparents have a probability of heterozygosity of 0.5. Fourteen ataxia-telangiectasia patients had died by June 30, 1986. This was a significant excess (14 deaths observed, 1.65 expected). Only one death was from a malignancy (non-Hodgkin's lymphoma). Three parents of ataxia-telangiectasia patients had died, all from cancer. The excess from breast cancer (two deaths observed, 0.17 expected) was statistically significant, p less than 0.05. However, no excess mortality from malignant neoplasms was found in the grandparents. Five xeroderma pigmentosum patients had died, none from internal malignancies. No excess mortality from malignant neoplasms was recorded in either their parents or grandparents.
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PMID:Cancer in homozygotes and heterozygotes of ataxia-telangiectasia and xeroderma pigmentosum in Britain. 335 49

Women with breast cancer and a family history of breast cancer and some with sporadic breast cancer are deficient in the repair of radiation-induced DNA damage compared with normal donors with no family history of breast cancer. DNA repair was measured indirectly by quantifying chromatid breaks in phytohaemagglutinin (PHA)-stimulated blood lymphocytes after either X-irradiation or UV-C exposure, with or without post treatment with the DNA repair inhibitor, 1-beta-D-arabinofuranosylcytosine (ara-C). We have correlated chromatid breaks with unrepaired DNA strand breaks using responses to X-irradiation of cells from xeroderma pigmentosum patients with well-characterised DNA repair defects or responses of repair-deficient mutant Chinese hamster ovary (CHO) cells with or without transfected human DNA repair genes. Deficient DNA repair appears to be a predisposing factor in familial breast cancer and in some sporadic breast cancers.
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PMID:Deficient DNA repair capacity, a predisposing factor in breast cancer. 867 41

A human cDNA previously isolated by virtue of its ability to complement partially the ultraviolet sensitivity of a xeroderma pigmentosum cell line was further characterized. The transcription unit is expressed as a single 4.0-kb mRNA that encodes a novel 63-kDa cytoplasmic protein, possibly initiating from an internal AUG codon. The gene encoding this protein, named UVRAG, has been extremely well conserved during evolution, implying an important role for this gene product in cell metabolism. The transcribed mRNA is constitutively expressed in a wide variety of human tissues. The protein encoded by this gene is predicted to contain a coiled-coil structure and is likely to be metabolically unstable based on the occurrence of a strong PEST domain. UVRAG was assigned to human chromosome 11 by Southern hybridization to a somatic cell hybrid panel. Fluorescence in situ hybridization coupled with PCR analysis of human/rodent somatic cell hybrids containing segments of human chromosome 11 has localized this gene to a subregion of 11q13 in between the D11S916 and the D11S906 loci. Importantly, this region has been shown to be amplified in a variety of human malignancies, including breast cancer.
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PMID:Molecular cloning of a novel human gene encoding a 63-kDa protein and its sublocalization within the 11q13 locus. 916 38

The mutagen sensitivity assay is one of the approaches used to investigate individual DNA repair capacity. This method is based on the premise that after in vitro treatment with a test mutagen, DNA from subjects with defective repair will be more damaged than DNA from those with an efficient repair system. However, very little is known about unmeasured processes that occur between cell treatment and final assessment of DNA damage. To develop a more precise assay, we modified the traditional mutagen sensitivity assay to also include measurement of DNA damage after culturing cells in the absence of mutagen. First, we treated apparently normal and xeroderma pigmentosum lymphoblastoid cell lines with various doses of benzo(a)pyrene diol epoxide (BPDE) and harvested cells at different time points. A polyclonal antiserum against BPDE-DNA was used to quantitate levels of adducts by immunoslot-blot and immunohistochemistry. Selected conditions included treatment with 10 microM BPDE, a 4-hr culture in mutagen-free medium, and immunohistochemical measurement of BPDE-DNA adducts. The method was then applied in a pilot study to 50 lymphoblastoid lines from sisters discordant for breast cancer. There was no significant difference between cases and controls in the level of BPDE-DNA adducts in lymphoblasts harvested immediately after BPDE treatment. However, after a 4-hr culture in mutagen-free medium, the level of adducts was significantly higher (P = 0.006) among cases than in controls. There was a two-fold increase in mean adduct removal in lines from nonaffected as compared to affected sisters (44% and 22% decrease, respectively). DNA repair capacity was predictive of case status (P = 0.04) in logistic regression analysis. This method, which can be easily applied to large numbers of samples, should be useful in studies to investigate the role of DNA repair in cancer risk.
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PMID:Removal of benzo(a)pyrene diol epoxide (BPDE)-DNA adducts as a measure of DNA repair capacity in lymphoblastoid cell lines from sisters discordant for breast cancer. 1220 1

Exposure to UVB results in formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts in DNA. These can be quantified by a variety of techniques including alkaline gel electrophoresis, ELISAs, Southwestern blotting, and immunohistochemistry. Damage to DNA results in activation of damage response pathways, as indicated by Western blotting using antibodies specific for p53 and breast cancer-associated gene 1 (BRCA1) phosphorylation. The signal from DNA damage to activation of these response pathways appears to be mediated by FKBP12-rapamycin-associated protein (FRAP), since these phosphorylation events are blocked by rapamycin. UVB-induced DNA damage also leads to induction of immunosuppressive cytokines including tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-10 in skin. Induction of TNF-alpha by UVB is readily detectable in cultured normal human epidermal keratinocytes (NHEKs) using ELISA, while induction of IL-10 is readily detectable in cultured mouse keratinocytes but not in NHEKs. Induction of DNA damage by liposome-encapsulated HindIII results in induction of immunosuppressive responses similar to UVB. Clinical testing shows that liposome-encapsulated T4 endonuclease V or photolyase stimulates repair of CPDs in the skin of human subjects, and prevents UVB-induced immunosuppression. Stimulation of repair and prevention of immunosuppression have been linked to prevention of skin cancer by liposome-encapsulated T4 endonuclease V in repair-deficient xeroderma pigmentosum patients.
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PMID:Measurement of UVB-Induced DNA damage and its consequences in models of immunosuppression. 1223 Nov 88

Cellular and humoral defence mechanisms are essential for the survival of individuals and species. Thus, DNA repair prevents mutations and cytotoxicity from DNA damage, thereby reducing the risks of inappropriate cell death, developmental defects, premature ageing and cancer. Similarly, antigen-dependent acquired immune responses prevent infections and also have a role in cancer prevention. DNA repair is highly complex and functions in an intricate network that also involves transcription, replication, cell cycle regulation, and the immune system. DNA damage is repaired by at least four major mechanisms, each requiring many different proteins. In addition there are "subpathways", and back-up mechanisms both within and between pathways. Various defects in DNA repair result in different forms of cancer, e.g. the rare syndrome Xeroderma pigmentosum and the more common diseases early-onset breast cancer and hereditary non-polyposis colon cancer. Surprisingly, recent research has revealed molecular interactions between the ancient DNA repair mechanisms and the much younger acquired immune system. Thus, the classical base excision enzyme uracil-DNA glycosylase encoded by the UNG gene is also involved in somatic hypermutation and class switch recombination, e.g. from IgM antibodies to IgG, yielding secreted high affinity antibodies. Mutations in both alleles of UNG result in a hyper-IgM syndrome with life-threatening infections. Furthermore, it has recently become clear that not only DNA, but also RNA and proteins are repaired. Thus, certain aberrant methylations in RNA are repaired by oxidative demethylation in one step restoring the normal base, and at least in a bacterial model system this increases survival several-fold after exposure to methylating agents. Proteins are repaired both at the peptide amino acid level and at the structural level. RNA and protein repair are likely to be important to prevent the formation of cytotoxic protein aggregates of the types known to cause neurodegenerative diseases e.g. Alzheimer's, Parkinson's and Huntington's diseases, and other diseases as well. In conclusion, recent research has demonstrated an unexpected complexity of cellular defence mechanisms that function in intricate networks, rather than as independent mechanisms. The new knowledge opens for interventions that are based on a deeper understanding of the mechanisms of defence.
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PMID:Novel aspects of macromolecular repair and relationship to human disease. 1498 56

A substantial proportion of the familial risk of breast cancer may be due to genetic variants, each contributing a small effect. The protein encoded by ERCC2 is a key enzyme involved in nucleotide excision repair, in which gene defects could lead to cancer prone syndromes such as Xeroderma pigmentosum D. We have examined the association between single nucleotide polymorphisms in the ERCC2 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3,634 patients and of 3,340 controls. None of the three single nucleotide polymorphisms were significantly associated with the incidence of breast cancer.
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PMID:Common polymorphisms in ERCC2 (Xeroderma pigmentosum D) are not associated with breast cancer risk. 1603 Jan 24

Many industrial and agricultural chemicals have steroid hormone agonist or antagonist activities and disrupt hormone-regulated gene expression. The widely-used agricultural insecticide, diazinon, was evaluated using MCF-7 cells - a breast cancer-derived, estrogen-dependent, human cell line - to examine the capacity of this chemical to alter steroid hormone-regulated gene expression. MCF-7 cells were treated with 30, 50, or 67 ppm of diazinon, and gene expression in treated cells was measured as mRNA levels in the cells compared to mRNA levels in untreated or estrogen-treated cells. DNA microarray analysis showed significant up- or down-regulation of a number of genes in treated cells compared to untreated cells. Of the 600 human genes on the chip utilized, specific genes with related functions were selected for additional consideration. Real time quantitative PCR (qrtPCR) completed to corroborate mRNA levels as a measure of specific gene expression, confirmed results obtained from analysis of the micro-array data. The data show that ERCC5, encoding Xeroderma pigmentosum protein G (XPG), essential for DNA excision repair, and ribonucleotide reductase subunit M1 (RNRM1), encoding a gene necessary for providing the nucleotides needed for DNA repair, were down-regulated in cells treated with diazinon. These studies were designed to provide base-line data on the gene expression-altering capacity of a specific agricultural chemical, diazinon, and allow assessment of some of the potentially deleterious effects associated with exposure of human cells to diazinon.
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PMID:Altered gene expression in human cells treated with the insecticide diazinon: correlation with decreased DNA excision repair capacity. 1653 10

Interindividual differences in DNA repair capacity (DRC) may play a critical role in breast cancer risk. Previously, we determined that DRC measured via removal of in vitro-induced benzo[a]pyrene diolepoxide-DNA adducts in lymphoblastoid cell lines was lower in cases compared with controls among sisters discordant for breast cancer from the Metropolitan New York Registry of Breast Cancer Families. We have now determined genotypes for seven single nucleotide polymorphisms in five nucleotide excision repair genes, including Xeroderma pigmentosum complementation group A (XPA +62T>C), group C (XPC Lys939Gln and Ala499Val), group D (XPD Asp312Asn and Lys751Gln), and group G (XPG His1104Asp) and ERCC1 (8092 C>A) in a total of 160 sister pairs for whom DRC phenotype data were available. Overall, there were no statistically significant differences in average DRC for most of the genotypes. A final multivariate conditional logistic model, including three single nucleotide polymorphisms (XPA +62T>C, XPC Ala499Val, and XPG His1104Asp) and smoking status, only modestly predicted DRC after adjusting for case-control status and age of blood donation. The overall predictive accuracy was 61% in the model with a sensitivity of 78% and specificity of 39%. These findings suggest that those polymorphisms we have investigated to date in nucleotide excision repair pathway genes explain only a small amount of the variability in DRC.
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PMID:Polymorphisms in nucleotide excision repair genes and DNA repair capacity phenotype in sisters discordant for breast cancer. 1698 21

It was not known how xeroderma pigmentosum group C (XPC) protein, the primary initiator of global nucleotide excision repair, achieves its outstanding substrate versatility. Here, we analyzed the molecular pathology of a unique Trp690Ser substitution, which is the only reported missense mutation in xeroderma patients mapping to the evolutionary conserved region of XPC protein. The function of this critical residue and neighboring conserved aromatics was tested by site-directed mutagenesis followed by screening for excision activity and DNA binding. This comparison demonstrated that Trp690 and Phe733 drive the preferential recruitment of XPC protein to repair substrates by mediating an exquisite affinity for single-stranded sites. Such a dual deployment of aromatic side chains is the distinctive feature of functional oligonucleotide/oligosaccharide-binding folds and, indeed, sequence homologies with replication protein A and breast cancer susceptibility 2 protein indicate that XPC displays a monomeric variant of this recurrent interaction motif. An aversion to associate with damaged oligonucleotides implies that XPC protein avoids direct contacts with base adducts. These results reveal for the first time, to our knowledge, an entirely inverted mechanism of substrate recognition that relies on the detection of single-stranded configurations in the undamaged complementary sequence of the double helix.
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PMID:An aromatic sensor with aversion to damaged strands confers versatility to DNA repair. 1735 81


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