Breast Cancer Risk Is Associated with the Genes Encoding the DNA Double-Strand Break Repair Mre11/Rad50/Nbs1 Complex

Abstract

The evolutionarily conserved Mre11-Rad50-Nbs1 (MRN) complex, consisting of proteins encoded by the genes Mre11, Rad50, and Nbs1, was recently shown to play a crucial role in DNA double-strand break (DSB) repair by recruiting the nuclear protein kinase ataxia telangiectasia mutated to DSB sites, leading to activation of this DNA repair network. Given the fact that carriers of defective mutation and polymorphic variants of ataxia telangiectasia mutated are at higher risk of developing breast cancer, we hypothesized a role of the MRN genes in determining breast cancer susceptibility. This hypothesis was examined both in a case control study of 559 breast cancer patients and 1,125 healthy women of single-nucleotide polymorphisms in Mre11, Rad50, and Nbs1 and by the in vivo detection of binding between Mre11 and BRCA1, encoded by the breast cancer susceptibility gene BRCA1. We were also interested in defining whether any association between MRN genes and breast cancer was modified by reproductive risk factors reflecting the level of estrogen exposure or susceptibility to estrogen exposure, as estrogen is known to initiate breast cancer development due to its metabolites causing DSB formation. Support for the hypothesis came from the observations that (a) one single-nucleotide polymorphism in Nbs1 was significantly associated with breast cancer risk, and a trend toward an increased risk of developing breast cancer was found in women harboring a greater number of putative high-risk genotypes of MRN genes (an adjusted odds ratio of 1.25 for each additional putative high-risk genotype; 95% confidence interval, 1.10-1.44); (b) this association between risk and the number of putative high-risk genotypes was stronger and more significant in women thought to be more susceptible to estrogen, i.e., those with no history of full-term pregnancy, those older (z26 years of age) at first full-term pregnancy, or those having had fewer (<2) full-term pregnancies; the risk effect conferred by harboring a higher number of high-risk genotypes of MRN genes was more significant in women without a history of breast feeding; and (c) Mre11 and BRCA1 were shown to form a complex in vivo, and this interaction was increased by irradiation. This study supports the role of the MRN pathway in breast cancer development, further strengthening the suggestion that mechanisms regulating DSB repair may play a mutator role driving breast cancer pathogenesis. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2024 -32)

Transcriptome-guided characterization of genomic rearrangements in a breast cancer cell line

“…For example, MRE11A, a key component of the DNA mismatch repair pathway, functions in DNA double-strand break repair. It has been reported to accumulate somatic mutations that lead to truncations of its protein in many types of tumors, including breast cancer (16)(17)(18)(19)(20)(21)(22)(23)(24). In the HCC1954 cancer cell line, this gene is truncated at its DNA binding domain because of a translocation event between chromosomes 11 and 4 (Fig.…”

Genetic Variants of NBS1 Predict Clinical Outcome of Platinum-based Chemotherapy in Advanced Non-small Cell Lung Cancer in Chinese

“…Publications on NBS1 polymorphisms have mainly focused on rs1805794 and the risk of cancers including lung, breast, bladder, renal cell cancers, non-Hodgkin lymphoma and childhood acute leukemia (Medina et al, 2003;Lan et al, 2005;Zienolddiny, 2005;Landi et al, 2006;Ryk et al, 2006;Hsu et al, 2007;Choudhury et al, 2008;Margulis et al, 2008;Mosor et al, 2008;Schuetz et al, 2009;Stern et al, 2009;Park et al, 2010), but the results were not consistent. A recent meta-analysis on rs1805794 has shed light on a positive association between the variant genotype of rs1805794 and the risk of multiple cancers (MeiXia et al, 2009).…”

“…Rs1805794 located in exon 5 of NBS1 is one of the most common polymorphisms and can induce an amino acid substitution from Glu to Gln. Studies have investigated the association between rs1805794 and risk of multiple cancers, such as lung, breast, bladder and nasopharyngeal carcinoma (Medina et al, 2003;Lan et al, 2005;Lu et al, 2006;Hsu et al, 2007;Stern et al, 2009;Zheng et al, 2011). However, only one study has explored the effect of this polymorphism on prognosis of human cancer and reported that it was not associated with the survival of esophagus or gastric adenocarcinoma after platinum-based neoadjuvant poly-chemotherapy (Ott et al, 2011).…”

Hereditary breast and ovarian cancer susceptibility genes (Review)

“…RAD genes are involved in DNA DSB repair and required for both (62,63) types of the repair processes, NHEJ and HR (60). Polymorphic variants and defective mutations of RAD50 may be at a risk of developing breast cancer possibly through the loss-of-function of the MRE11-RAD50-NBN complex, key factors in maintaining genome stability (61). Some patients with an HBOC-like phenotype have mutations in RAD50.…”