ArticleMolecular oncology2008
Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene.
Article in Molecular oncology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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87 citing papers in PubMed, 160 citations in OpenAlex.
- MRE11 deacetylation by SIRT2 promotes DNA binding to facilitate DNA end resection and ATM-dependent signaling.The Journal of clinical investigation · 2026Article
- Contribution of MRE11, RAD50, and NBS1 Genotypes to Bladder Cancer Susceptibility.Cancer genomics & proteomics · 2025Article
- Molecule subtypes play important roles for second primary malignancies development based on 324,661 breast cancer survivors.Scientific reports · 2025Article
- To cleave or not and how? The DNA exonucleases and endonucleases in immunity.Genes & diseases · 2025Review
- Impact of Molecular Profiling on Therapy Management in Breast Cancer.Journal of clinical medicine · 2024Review
- Predictive modeling of gene mutations for the survival outcomes of epithelial ovarian cancer patients.PloS one · 2024Article
- Interactions between the DNA Damage Response and the Telomere Complex in Carcinogenesis: A Hypothesis.Current issues in molecular biology · 2023Review
- Integrating somatic CNV and gene expression in breast cancers from women with PTEN hamartoma tumor syndrome.NPJ genomic medicine · 2023Article
- Importance of Germline and Somatic Alterations in HumanInternational journal of molecular sciences · 2023Review
- Article
- Crosstalk between SUMOylation and ubiquitylation controls DNA end resection by maintaining MRE11 homeostasis on chromatin.Nature communications · 2022Article
- Exome sequencing reveals a distinct somatic genomic landscape in breast cancer from women with germline PTEN variants.American journal of human genetics · 2022Article
- Germline Mutation Analysis in Sporadic Breast Cancer Cases With Clinical Correlations.Frontiers in genetics · 2022Article
- Suppression of isoprenylcysteine carboxylmethyltransferase compromises DNA damage repair.Life science alliance · 2021Article
- Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers.NPJ breast cancer · 2021Article
- Homologous Recombination Deficiency: Cancer Predispositions and Treatment Implications.The oncologist · 2021Review
- Germline risk of clonal haematopoiesis.Nature reviews. Genetics · 2021Review
- Review
- Review
- Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?International journal of molecular sciences · 2020Review
27 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 3 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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