UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inherited mutations in BRCA1 predispose to breast and ovarian cancer, but the biological function of the BRCA1 protein has remained largely elusive. The recent correspondence of Koonin et al. [Koonin, E.V., Altschul, S.F. and Bork, P. (1996) Nature Genet. 13, 266-267] has emphasized the potential importance of the BRCA1 C-terminal region for BRCA1-mediated breast cancer suppression, as this domain shows similarities with the C-terminal regions of a p53-binding protein (53BP1), the yeast RAD9 protein involved in DNA repair, and two uncharacterized, hypothetical proteins (KIAA0170 and SPAC19G10.7). The highlighted domain has been suggested to be the result of an internal duplication, each of the tandem domains being designated as a 'BRCT domain' (for BRCA1 C-terminus). Sequence analysis using hydrophobic cluster analysis reveals here the presence of 50 copies of the BRCT domain in 23 different proteins, including, in addition to BRCA1, 53BP1 and RAD9, XRCC1, RAD4, Ect2, REV1, Crb2, RAP1, terminal deoxynucleotidyltransferases (TdT) and three eukaryotic DNA ligases. Most of these proteins are known to be involved in DNA repair. The BRCT domain is not limited to the C-termini of protein sequences and can be found in multiple copies or in a single copy as in RAP1 and TdT, suggesting that it could well constitute an autonomous folding unit of approx. 90-100 amino acids.
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PMID:From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair. 900 May 7

The BRCT domain (BRCA1 C-terminus), first identified in the breast cancer suppressor protein BRCA1, is an evolutionarily conserved protein-protein interaction region of approximately 95 amino acids found in a large number of proteins involved in DNA repair, recombination and cell cycle control. Here we describe the first three-dimensional structure and fold of a BRCT domain determined by X-ray crystallography at 3.2 A resolution. The structure has been obtained from the C-terminal region of the human DNA repair protein XRCC1, and comprises a four-stranded parallel beta-sheet surrounded by three alpha-helices, which form an autonomously folded domain. The compact XRCC1 structure explains the observed sequence homology between different BRCT motifs and provides a framework for modelling other BRCT domains. Furthermore, the established structure of an XRCC1 BRCT homodimer suggests potential protein-protein interaction sites for the complementary BRCT domain in DNA ligase III, since these two domains form a stable heterodimeric complex. Based on the XRCC1 BRCT structure, we have constructed a model for the C-terminal BRCT domain of BRCA1, which frequently is mutated in familial breast and ovarian cancer. The model allows insights into the effects of such mutations on the fold of the BRCT domain.
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PMID:Structure of an XRCC1 BRCT domain: a new protein-protein interaction module. 979 48

XRCC1 (X-ray cross-complementing group 1) is a DNA repair protein that forms complexes with DNA polymerase beta (beta-Pol), DNA ligase III and poly-ADP-ribose polymerase in the repair of DNA single strand breaks. The domains in XRCC1 have been determined, and characterization of the domain-domain interaction in the XRCC1-beta-Pol complex has provided information on the specificity and mechanism of binding. The domain structure of XRCC1, determined using limited proteolysis, was found to include an N-terminal domain (NTD), a central BRCT-I (breast cancer susceptibility protein-1) domain and a C-terminal BRCT-II domain. The BRCT-I-linker-BRCT-II C-terminal fragment and the linker-BRCT-II C-terminal fragment were relatively stable to proteolysis suggestive of a non-random conformation of the linker. A predicted inner domain was found not to be stable to proteolysis. Using cross-linking experiments, XRCC1 was found to bind intact beta-Pol and the beta-Pol 31 kDa domain. The XRCC1-NTD(1-183)(residues 1-183) was found to bind beta-Pol, the beta-Pol 31 kDa domain and the beta-Pol C-terminal palm-thumb (residues 140-335), and the interaction was further localized to XRCC1-NTD(1-157)(residues 1-157). The XRCC1-NTD(1-183)-beta-Pol 31 kDa domain complex was stable at high salt (1 M NaCl) indicative of a hydrophobic contribution. Using a yeast two-hybrid screen, polypeptides expressed from two XRCC1 constructs, which included residues 36-355 and residues 1-159, were found to interact with beta-Pol, the beta-Pol 31 kDa domain, and the beta-Pol C-terminal thumb-only domain polypeptides expressed from the respective beta-Pol constructs. Neither the XRCC1-NTD(1-159), nor the XRCC1(36-355)polypeptide was found to interact with a beta-Pol thumbless polypeptide. A third XRCC1 polypeptide (residues 75-212) showed no interaction with beta-Pol. In quantitative gel filtration and analytical ultracentrifugation experiments, the XRCC1-NTD(1-183)was found to bind beta-Pol and its 31 kDa domain in a 1:1 complex with high affinity (K(d) of 0.4-2.4 microM). The combined results indicate a thumb-domain specific 1:1 interaction between the XRCC1-NTD(1-159)and beta-Pol that is of an affinity comparable to other binding interactions involving beta-Pol.
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PMID:Domain specific interaction in the XRCC1-DNA polymerase beta complex. 1077 72

Proteins involved in DNA repair, or its coordination with DNA replication and mitosis through cell cycle checkpoints, are vital in the concerted cellular response to DNA damage that maintains the integrity of the genome. The "BRCT" domain (BRCA1 carboxy terminal) was noted as a putative protein-protein interaction motif in the breast cancer suppressor gene, BRCA1, and subsequently identified in over 50 proteins involved in DNA repair, recombination, or cell cycle control. The heterodimer of the DNA repair proteins, XRCC1 and DNA ligase III, was the first example of a functional interaction via BRCT modules. The only three-dimensional crystal structure of a BRCT domain was solved for this region of XRCC1. Key amino acid residues mediating the interaction with DNA ligase III were identified here by targeted mutagenesis of the XRCC1 BRCT domain. The consequences of these mutations on protein folding were assessed. A structural model of the DNA ligase III BRCT domain was constructed and similarly tested by mutation of corresponding residues required for the interaction with XRCC1. These data identify the XRCC1-DNA ligase III heterodimer interface and provide the first demonstration of the surface contacts coordinating a functional BRCT-BRCT protein interaction.
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PMID:BRCT domain interactions in the heterodimeric DNA repair protein XRCC1-DNA ligase III. 1135 25

Genetic variability in DNA repair may contribute to hypersensitivity to ionizing radiation (IR) and susceptibility to breast cancer. We used samples collected from a clinic-based breast cancer case-control study to test the working hypothesis that amino acid substitution variants of DNA repair genes may contribute to prolonged cell-cycle delay following IR and breast cancer risk. Fluorescence-activated cell sorter (FACS) analysis was used to measure cell-cycle delay. PCR-restriction fragment length polymorphism (RFLP) assays were used to determine four genotypes of three DNA repair genes: XRCC1, 194 Arg/Trp and 399 Arg/Gln; XRCC3, 241 Thr/Met; and APE1, 148 Asp/Glu. The data showed that breast cancer patients had a significantly higher delay index than that of controls (P < 0.001); the means +/- SD for cases and controls were 36.0 +/- 13.1 (n = 118) and 31.4 +/- 11.5 (n = 225), respectively. There was a significant dose-response relationship between delay index, categorized into quartiles, and an increasing risk of breast cancer (crude odds ratios: 1.00, 1.00, 1.27, and 2.46, respectively; P(trend) = 0.002). In controls, prolonged cell-cycle delay was significantly associated with the number of variant alleles in APE1 Asp148Glu and XRCC1 Arg399Gln genotypes (P(trend) = 0.001). Although larger studies are needed to validate the results, our data suggest that an inherited hypersensitivity to IR may contribute to human breast carcinogenesis.
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PMID:Genetic regulation of ionizing radiation sensitivity and breast cancer risk. 1192 Nov 91

XRCC1 (X-ray repair cross-complementing group 1) is a base excision repair protein that plays a central role in the repair of DNA strand breaks and base damage from a variety of endogenous and exogenous oxidants including tobacco smoke. One genetic polymorphism (G-->A, Arg-->Gln at codon 399) occurs within a poly(ADP-ribose) polymerase binding region and within the central breast cancer susceptibility gene 1 product COOH terminus domain of XRCC1. The variant 399Gln allele of XRCC1 has been associated with elevated biomarkers of DNA damage in human cells. We conducted an analysis of the Arg399Gln polymorphism in XRCC1 using genomic DNA, and questionnaire information from 309 cases of pancreatic adenocarcinoma and 964 controls that were part of a population-based, case-control study conducted in the San Francisco Bay Area between 1994 and 2001. We genotyped individuals using a mass spectrometry-based method. Because smoking and obesity are known and suspected pancreas cancer risk factors, and have been associated with DNA damage and oxidative stress in target tissues, we estimated odds ratios (ORs), interaction contrast ratios (ICRs), and 95% confidence intervals for the combined effects of XRCC1 genotype and smoking or body mass index (in kg/m(2)). We also assessed potential gene-gene interactions between polymorphisms in XRCC1 and CYP1A1, GSTT1, and GSTM1. We found little or no evidence for an association between XRCC1 genotype and pancreatic cancer among Caucasians, African-Americans, or Asians. There was evidence for interaction between XRCC1 399Gln and smoking that was stronger among women than men. Relative to never active or passive smokers with the Arg/Arg genotype, the age- and race-adjusted ORs and ICRs (95% confidence limits) for heavy smoking (>or=41 pack-years) were: for Gln/Gln or Arg/Gln genotypes [women OR = 7.0 (2.4, 21), ICR = 3.1 (0.03, 6.2); men OR = 2.4 (1.1, 5.0), ICR = 1.3 (-0.20, 2.8)]; and for the Arg/Arg genotype [women OR = 2.2 (0.73, 6.4); men OR = 1.5 (0.68, 3.2)]. Analyses of combined genotypes suggested an interaction between XRCC1 (Gln/Gln or Arg/Gln) and GSTT1/GSTM1-null/null among women but not among men. There was no evidence of interaction between XRCC1 genotype and body mass index. Our results suggest that the XRCC1 399Gln allele is a potentially important determinant of susceptibility to smoking-induced pancreatic cancer. Our findings, including stronger associations and interactions among women, require replication in additional study populations.
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PMID:A population-based study of the Arg399Gln polymorphism in X-ray repair cross- complementing group 1 (XRCC1) and risk of pancreatic adenocarcinoma. 1218 19

Common polymorphisms in DNA repair genes may alter protein function and an individual's capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. To establish our overall understanding of possible in vivo relationships between DNA repair polymorphisms and the development of cancer, we performed a literature review of epidemiological studies that assessed associations between such polymorphisms and risk of cancer. Thirty studies of polymorphisms in OGG1, XRCC1, ERCC1, XPC, XPD, XPF, BRCA2, and XRCC3 were identified in the April 30, 2002 MEDLINE database (National Center for Biotechnology Information. PubMed Database: http://www.ncbi.nlm.nih.gov/entrez). These studies focused on adult glioma, bladder cancer, breast cancer, esophageal cancer, lung cancer, prostate cancer, skin cancer (melanoma and nonmelanoma), squamous cell carcinoma of the head and neck, and stomach cancer. We found that a small proportion of the published studies were large and population-based. Nonetheless, published data were consistent with associations between: (a) the OGG1 S326C variant and increased risk of various types of cancer; (b) the XRCC1 R194W variant and reduced risk of various types of cancer; and (c) the BRCA2 N372H variant and increased risk of breast cancer. Suggestive results were seen for polymorphisms in other genes; however, small sample sizes may have contributed to false-positive or false-negative findings. We conclude that large, well-designed studies of common polymorphisms in DNA repair genes are needed. Such studies may benefit from analysis of multiple genes or polymorphisms and from the consideration of relevant exposures that may influence the likelihood of cancer in the presence of reduced DNA repair capacity.
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PMID:Polymorphisms in DNA repair genes and associations with cancer risk. 1249 39

Breast cancer is the most prevalent cancer among women in Western countries, and its prevalence is also increasing in Asia. The major risk factor for breast cancer can be traced to reproductive events that influence the lifetime levels of hormones. However, a large percentage of breast cancer cases cannot, be explained by these risk factors. The identification of susceptibility factors that predispose individuals to breast cancer (for instance, if they are exposed to particular environmental agents) could possibly give further insight into the etiology of this malignancy and provide targets for the future development of therapeutics. The most interesting candidate genes include those that mediate a range of functions. These include carcinogen metabolism, DNA repair, steroid hormone metabolism, signal transduction, and cell cycle control. we conducted a hospital-based case-control study on South Korea to evaluate the potential modifying role of the genetic pollymprphisms of selected low penetrance gens that are involved carcinogen metabolisms (i.e., CYP1A1, CYP2E1, GSTM1/T1/P1, NAT1/2, etc.), estrogen synthesis and metabolism (i.e., CYP19, CYP17, CYP1B1, COMT, ER-alpha, etc.), DNA repair (i.e., XRCC1/3, ERCC2/4, ATM, AGT, etc.), and signal transduction as well as others (i.e., TGF- beta, IGF-1, TNF- beta, IL-1B, IL-1RN, etc.). We also took into account the potential interaction between these and the known risk factors of breast cancer. The results of selected genes will be presented in this mini-review.
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PMID:Genetic polymorphisms and cancer susceptibility of breast cancer in Korean women. 1254 72

Mammalian cells are constantly exposed to a wide variety of genotoxic agents from both endogenous and exogenous sources. Genetic variability in DNA repair may contribute to human cancer risk. We used a case-control study design (162 cases and 302 controls) to test the association between three amino acid substitution variants of DNA repair genes (XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 Thr241Met) and breast cancer susceptibility. We found a weak association between the XRCC1 194Trp allele and breast cancer risk (adjusted odds ratio (OR)=1.98; 95% confidence interval (CI)=0.85-4.63). We also found a potential gene-gene interaction between the XRCC1 194Trp allele and XRCC3 241Met allele and breast cancer risk (adjusted OR=8.74; 95% CI=1.13-67.53). Although larger studies are needed to validate the study results, our data suggest that amino acid substitution variants of XRCC1 and XRCC3 genes may contribute to breast cancer susceptibility.
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PMID:Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer. 1256 73

As a cause of death in women, breast cancer ranks second to stomach cancer in Korea. Age-standardized mortality rates for breast cancer steadily increased during the 1980s and 1990s. There are big differences in the incidence rates for breast cancer compared with Western countries. Epidemiological features, trends in morbidity and mortality, various age-specific incidence curves, migrant study results, and analysis of the risk factors, however, suggest that the incidence of breast cancer might be further increasing in Korea. The key epidemiological hormonal risk factors for breast cancer are all explicable in terms of the estrogen augmented by progesterone hypothesis. These include older age, family history of breast cancer, early menarche, late menopause, late full-term pregnancy, and never a breast feeding. Both the establishment of high-risk groups and the estimation of lifetime risk are essential to develop a control strategy against breast cancer. Invasive ductal carcinoma is the most common histologic type of breast cancer in Korea, and the five-year survival rate has been estimated as 80-83%. Recent studies on the identification of susceptibility factors such as genetic polymorphisms of GSTM1/T1/P1, COMT, CYP2E1, CYP19, CYP17, ER-alpha, XRCC1, XRCC3, RAD52, TGF-alpha, TNF-alpha, IL-1B, IL-1RN, CDK7 etc. that predispose individuals to breast cancer by gene-environment or gene-gene interactions may possibly give further insight into both the etiology and the prevention of this malignancy.
Breast Cancer 2003
PMID:Current researches on breast cancer epidemiology in Korea. 1463 5

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