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)

The MRN protein complex, consisting of MRE1, RAD50 and NBS1, plays a crucial role in sensing DNA double-strand breaks (DSBs), and it is involved in cell cycle control. This makes the MRN complex an important guard of genome stability. Hypomorphic mutations in NBS1 result in the Nijmegen breakage syndrome (NBS), which is characterized by, among other things, an increased predisposition to malignancies, especially leukemia/lymphoma. Relatives of NBS patients carrying heterozygous mutations are also more prone to cancer development. This review summarizes several studies searching for associations between heterozygous mutations in NBS1, MRE11, and RAD50 and cancer and examining the levels of expression of proteins coded by these genes in tumor tissues. The results indicate that both decreased and increased expression of NBS1 may contribute to tumorigenesis, whereas overexpressed RAD50 has an anti-tumoric effect. MRE11 and RAD50 are also affected in tumors with microsatellite instability. However, the outcomes of association studies, which concerned primarily lymphomas/leukemias and breast cancer, were inconclusive. Heterozygous NBS1 mutations and molecular variants 657del5, I171V, R215W and E185Q were most commonly analyzed. Among these, an association with cancer was found most frequently for 657del5 (in leukemia/lymphoma and breast cancer) and I171V (in leukemia, breast, head and neck and colorectal cancers); however, other studies gave contradictory results. For other NBS1 as well as MRE11 and RAD50 variants, too little data were available to assess their role in cancer risk. Overall, the results suggest that heterozygous MRN complex mutations and molecular variants may contribute only to a limited fraction of tumors. This may be caused by several factors: various frequencies of the variants in specific populations, different criteria used for selection of control groups, possible effects of environmental factors, and potential interactions with variants of other low-risk genes. These issues, as well as the impact of the alterations on protein function, need to be addressed in future studies.
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PMID:The importance of making ends meet: mutations in genes and altered expression of proteins of the MRN complex and cancer. 1860 67

Physical and chemical agents that induce DNA double-strand breaks (DSBs) are among the most potent mutagens. The mammalian cell response to DSB comprises a highly co-ordinated, yet complex network of proteins that have been categorized as sensors, signal transducers, mediators and effectors of damage and repair. While this provides an accessible classification system, review of the literature indicates that many proteins satisfy the criteria of more than one category, pointing towards a series of highly co-operative pathways with overlapping function. In summary, the MRE11-NBS1-RAD50 complex is necessary for achieving optimal activation of ataxia-telangiectasia-mutated (ATM) kinase, which catalyses a phosphorylation-mediated signal transduction cascade. Among the subset of proteins phosphorylated by ATM are histone H2AX (H2AX), mediator of damage checkpoint protein 1, nibrin (NBS1), P53-binding protein 1 and breast cancer protein 1, all of which subsequently redistribute into DSB-containing sub-nuclear compartments. Post-translational modification of DSB responding proteins achieves a rapid and reversible change in protein behaviour and mediates damage-specific interactions, hence imparting a high degree of vigilance to the cell. This review highlights events fundamental in maintaining genetic integrity with emphasis on early stages of the DSB response.
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PMID:Early events in the mammalian response to DNA double-strand breaks. 1864 34

Genetic variations in DNA repair may impact repair functions, DNA damage and breast cancer risk. Using data/samples collected from the first 752 Caucasians and 141 African-Americans in an ongoing case-control study, we examined the association between breast cancer risk and 18 non-synonymous single-nucleotide polymorphisms (nsSNPs) in four DNA repair pathways-(i) base excision repair: ADPRT V762A, APE1 D148E, XRCC1 R194W/R280H/R399Q and POLD1 R119H; (ii) nucleotide excision repair: ERCC2 D312N/K751Q, ERCC4 R415Q, ERCC5 D1104H and XPC A499V/K939Q; (iii) mismatch repair: MLH1 I219V, MSH3 R940Q/T1036A and MSH6 G39E and (iv) double-strand break repair: NBS1 E185Q and XRCC3 T241M. In Caucasians, breast cancer risk was significantly associated with ADPRT 762VV [odds ratio (OR) = 1.45; 95% confidence interval (CI) = 1.03, 2.03], APE1 148DD (OR = 1.44; 95% CI = 1.03, 2.00), MLH1 219II/IV (OR = 1.87; 95% CI = 1.11, 3.16) and ERCC4 415QQ (OR = 8.64; 95% CI = 1.04, 72.02) genotypes. With a limited sample size, we did not observe any significant association in African-Americans. However, there were significant trends in breast cancer risk with increasing numbers of risk genotypes for ADPRT 762VV, APE1 148DD, ERCC4 415RQ/QQ and MLH1 219II/IV (P(trend) < 0.001) in Caucasians and ADPRT 762VA, ERCC2 751KQ/QQ and NBS1 185EQ/QQ in African-Americans (P(trend) = 0.006), respectively. Our results suggest that combined nsSNPs in multiple DNA repair pathways may contribute to breast cancer risk and larger studies are warranted to further evaluate polygenic models of DNA repair in breast cancer risk.
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PMID:Polygenic model of DNA repair genetic polymorphisms in human breast cancer risk. 1870 35

CtIP, CtBP-interacting protein, is a nuclear protein that was identified as a cofactor for the transcriptional repressor CtBP. Our genetic studies in mice revealed that haploid insufficiency of CtIP leads to tumorigenesis and is associated with shortened life span. At the molecular level, CtIP is a multivalent adaptor. It interacts directly with pRB family members, the prototype tumor suppressor proteins, and contributes to G(1)/S regulation. It has also been implicated in DNA damage checkpoint control through its interaction with the breast cancer susceptibility gene product BRCA1. Recently, it was found to modulate the nuclease activity of the Mre11/Rad50/NBS1 complex. Here we report that CtIP is recruited to S-phase DNA replication foci through a novel motif functioning as replication foci targeting sequence (RFTS). This motif contains a consensus PCNA-interacting protein box that binds to PCNA both in vivo and in vitro. In support of the biological significance of this interaction, we detected arrest of the cell cycle at the S/G(2) phase transition, and suppression of cell proliferation in U2-OS cells upon the conditional expression of the wild type, but not a mutated RFTS using a tetracycline-inducible system. We found that cells expressing RFTS had excess DNA double strand breaks as demonstrated by formation of gamma-H2AX nuclear foci. Finally, G(2)/M checkpoint activation in response to the expression of the CtIP RFTS is abrogated by caffeine treatment. Our work suggests an intimate relationship between CtIP and PCNA may be important for the maintenance of genomic stability in higher eukaryotic organism.
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PMID:Expression of PCNA-binding domain of CtIP, a motif required for CtIP localization at DNA replication foci, causes DNA damage and activation of DNA damage checkpoint. 1934 88

The MRE11, RAD50, and NBS1 genes encode proteins of the MRE11-RAD50-NBS1 (MRN) complex critical for proper maintenance of genomic integrity and tumour suppression; however, the extent and impact of their cancer-predisposing defects, and potential clinical value remain to be determined. Here, we report that among a large series of approximately 1000 breast carcinomas, around 3%, 7% and 10% tumours showed aberrantly reduced protein expression for RAD50, MRE11 and NBS1, respectively. Such defects were more frequent among the ER/PR/ERBB2 triple-negative and higher-grade tumours, among familial (especially BRCA1/BRCA2-associated) rather than sporadic cases, and the NBS1 defects correlated with shorter patients' survival. The BRCA1-associated and ER/PR/ERBB2 triple-negative tumours also showed high incidence of constitutively active DNA damage signalling (gammaH2AX) and p53 aberrations. Sequencing the RAD50, MRE11 and NBS1 genes of 8 patients from non-BRCA1/2 breast cancer families whose tumours showed concomitant reduction/loss of all three MRN-complex proteins revealed two germline mutations in MRE11: a missense mutation R202G and a truncating mutation R633STOP (R633X). Gene transfer and protein analysis of cell culture models with mutant MRE11 implicated various destabilization patterns among the MRN complex proteins including NBS1, the abundance of which was restored by re-expression of wild-type MRE11. We propose that germline mutations qualify MRE11 as a novel candidate breast cancer susceptibility gene in a subset of non-BRCA1/2 families. Our data have implications for the concept of the DNA damage response as an intrinsic anti-cancer barrier, various components of which become inactivated during cancer progression and also represent the bulk of breast cancer susceptibility genes discovered to date.
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PMID:Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene. 1938 52

Inability to correctly repair DNA damage is known to play a role in the development of breast cancer. Single nucleotide polymorphisms (SNPs) of DNA repair genes have been identified, which modify the DNA repair capacity, which in turn may affect the risk of developing breast cancer. To assess whether alterations in DNA repair genes contribute to breast cancer, we genotyped 62 SNPs in 29 genes in 1,109 Cypriot women with breast cancer and 1,177 age-matched healthy controls. Five SNPs were associated with breast cancer. SNPs rs13312840 and rs769416 in the NBS1 gene were associated with a decrease in breast cancer risk (OR TT vs. TC/CC = 0.58; 95% CI, 0.37-0.92; P = 0.019 and OR GG vs. GT/TT = 0.23, 95% CI 0.06-0.85, P = 0.017, respectively). The variant allele of MRE11A rs556477 was also associated with a reduced risk of developing the disease (OR AA vs. AG/GG = 0.76; 95% CI, 0.64-0.91; P = 0.0022). MUS81 rs545500 and PBOV1 rs6927706 SNPs were associated with an increased risk of developing breast cancer (OR GG vs. GC/CC = 1.21, 95% CI, 1.02-1.45; P = 0.031; OR AA vs. AG/GG = 1.53, 95% CI, 1.07-2.18; P = 0.019, respectively). Finally, haplotype-based tests identified significant associations between specific haplotypes in MRE11A and NBS1 genes and breast cancer risk. Further large-scale studies are needed to confirm these results.
Breast Cancer Res Treat 2010 May
PMID:Genetic variation in genes interacting with BRCA1/2 and risk of breast cancer in the Cypriot population. 1971 62

The possible role for DNA repair deficiencies in cancer development, namely in breast cancer has been the subject of increasing interest since it has been reported that breast cancer patients might be deficient in the repair of DNA damage. Exposure to ionizing radiation has been pointed out as a risk factor for breast cancer, and the type of DNA lesions induced by this carcinogen can be repaired by homologous recombination DNA repair (HRR) pathway. To evaluate the potential modifying role of some single nucleotide polymorphisms (SNP) in HRR involved genes on the individual susceptibility to breast cancer we carried out a hospital based case-control study in a Caucasian Portuguese population (289 histological confirmed breast cancer patients and 548 control individuals). We genotyped 4 SNPs in 4 different HRR pathway genes, XRCC2 (Ex3+442G>A, R188H, rs3218536), XRCC3 (Ex8-5C>T, T241M, rs861539), NBS1 (Ex5-32C>G, E185Q, rs1805794) and RAD51 5'UTR (Ex1-59G>T, rs1801321), tagging 41 SNPs in these genes. The frequency of the different polymorphisms in the Portuguese control population is similar to the ones reported for other Caucasian populations, and the deviation of the Hardy-Weinberg equilibrium was only observed for the XRCC2 (Ex3+442G>A, R188H, rs3218536) polymorphism in the control population. The results obtained, after logistic regression analysis, did not reveal a major role of these polymorphisms on breast cancer susceptibility. However, when the population was stratified according to breast feeding (women that breast fed and women that never breast fed) it is observed, in women that never breast fed, that the heterozygous individuals for the XRCC2 (Ex3+442G>A, R188H, rs3218536) polymorphism have a decreased risk for breast cancer [adjusted OR=0.45; 95% CI=0.22-0.92] (P=0.03). Additionally, after stratification according to menopausal status, our results suggest that post-menopausal women carrying at least one variant allele for the XRCC3 (Ex8-5C>T, T241M, rs861539) polymorphism have a lower risk for breast cancer [adjusted OR=0.67; 95% CI, 0.47-0.94] (P=0.03). Most of the studies suggest that breastfeeding may be responsible for 2/3 of the estimate reduction of breast cancer. The longer the duration of breastfeeding the lower the potential risk associated with breast cancer. Therefore, in our study the potential protective role of the variant allele of XRCC2 (Ex3+442G>A, R188H, rs3218536), in never breast fed women, might be related with a more efficient DNA repair activity.
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PMID:Breast cancer risk and common single nucleotide polymorphisms in homologous recombination DNA repair pathway genes XRCC2, XRCC3, NBS1 and RAD51. 2000 34

NBS1 gene plays an important role in DNA repair. Many epidemiological studies have investigated the association between NBS1 8360G > C polymorphism and breast cancer, however, the results are still controversial. Therefore, we performed a meta-analysis of 10 case-control studies. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. The results showed NBS1 8360G > C polymorphism contributed to breast risk in overall populations (for CC vs. GG: OR = 0.75, 95% CI = 0.74-0.98, P = 0.13 for heterogeneity; for the recessive model CC vs. GG/CG: OR = 0.88, 95% CI = 0.77-1.00, P = 0.44 for heterogeneity). In subgroup analysis by ethnicity, no significant association was found in all genetic models. In summary, our meta-analysis strongly suggests the NBS1 8360G > C polymorphism is associated with breast cancer.
Breast Cancer Res Treat 2010 Sep
PMID:NBS1 8360G > C polymorphism is associated with breast cancer risk: a meta-analysis. 2132 67

To date, five moderate-risk breast cancer susceptibility genes have been convincingly identified: CHEK2, ATM, BRIP1, PALB2, and NBS1. Moderate-risk breast cancer alleles confer increased breast cancer risks of two to fourfold compared to the 10% risk in the general population. In contrast to the high-risk BRCA1 and BRCA2 genes, moderate-risk genes typically have a limited number of variants that confer breast cancer risks. The prevalence of the variants usually varies widely among different geographical or ethnic populations, ranging from essentially absent up to 1.5% (i.e. 'rare' variants). Since moderate-risk breast cancer alleles are clinically not recognizable when inherited as single mutant, one usually encounters them in a polygenic setting and consequently in incomplete cosegregation with the breast cancer phenotype. As a result, discovery of moderate-risk breast cancer genes requires conclusive statistical evidence from association studies of hundreds of breast cancer cases and population-matched controls.
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PMID:Discovering moderate-risk breast cancer susceptibility genes. 2034 47

Mammalian cells are frequently at risk of DNA damage from both endogenous and exogenous sources. Accordingly, cells have evolved the DNA damage response (DDR) pathways to monitor and assure the integrity of their genome. In cells, the intact and effective DDR is essential for the maintenance of genomic stability and it acts as a critical barrier to suppress the development of cancer in humans. Two central kinases for the DDR pathway are ATM and ATR, which can phosphorylate and activate many downstream proteins for cell cycle arrest, DNA repair, or apoptosis if the damages are irreparable. In the last several years, we and others have made significant progress to this field by identifying BRIT1 (also known as MCPH1) as a novel key regulator in the DDR pathway. BRIT1 protein contains 3 breast cancer carboxyl terminal (BRCT) domains which are conserved in BRCA1, MDC1, 53BP1, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. Our in vitro studies revealed BRIT1 to be a chromatinbinding protein required for recruitment of many important DDR proteins (ATM, MDC1, NBS1, RAD51, BRCA2) to the DNA damage sites. We recently also generated the BRIT1 knockout mice and demonstrated its essential roles in homologous recombination DNA repair and in maintaining genomic stability in vivo. In humans, BRIT1 is located on chromosome 8p23.1, where loss of hetero-zigosity is very common in many types of cancer. In this review, we will summarize the novel roles of BRIT1 in DDR, describe the relationship of BRIT1 deficiency with cancer development, and also discuss the use of synthetic lethality approach to target cancers with HR defects due to BRIT1 deficiency.
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PMID:Multiple roles of BRIT1/MCPH1 in DNA damage response, DNA repair, and cancer suppression. 2037 79


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