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 (>or=26 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.