Telomere length, oxidative damage, antioxidants and breast cancer risk

Telomeres are nucleotide repeats (TTAGGG)n with associated proteins at the ends of mammalian chromosomes. Telomeres play a critical role in maintaining the integrity and stability of the genome,1,2 and also participate in the process of cellular DNA damage/repair.3–5 In most proliferating cells, telomere length is dynamic, and subject to shortening at each cycle of cell division (the so-called end-replication problem).6 Telomere length measured in surrogate tissues, such as buccal cells, peripheral blood lymphocytes (PBLs), mononuclear cells and white blood cells (WBC) has been considered as one of the applicable susceptibility biomarkers for several kinds of human cancer,7–13 including breast cancer,14,15 but not all results are consistent.16–19 Levy and colleagues found that telomere length in WBC DNA was significantly shorter in breast cancer patients as compared with healthy individuals.14 A significantly reduced lymphocyte telomere length in breast cancer cases was noted in another study.15 However, when the cases and controls were better matched by age, no statistically significant difference in telomere length was detected.15 Three other studies, including ours, did not observe a significant relationship between shorter telomere length in peripheral blood cell DNA and overall breast cancer risk.16–18 One study even found a reverse effect, i.e. breast cancer patients displayed significantly longer telomere length compared with controls.19 None of these previous studies has analyzed the effect modification of DNA damage/repair on telomere length and breast cancer risk because of the lack of available data. DNA damage induced by oxidative stress is another mechanism involved in accelerated telomere shortening,20 and influences the relationship between telomere length and cancer risk. Telomeres as an initiator of DNA damage responses,21 play a significant role in distinguishing natural DNA ends from double-strand break ends that trigger DNA damage checkpoints and subsequent repair.3,22 Due to the high content of guanines, telomeres are especially sensitive to the accumulation of reactive oxygen species (ROS)-induced 8-oxo-7,8-dihydrodeoxyguanosine (8-oxodG) DNA-strand breaks.23–25 Exposure to oxidative stress can induce a higher level of 8-oxodG formation in the telomere sequences than in other non-telomere sequences.26,27 Besides the direct effect of oxidative damage on telomeric DNA, it has been proposed that deficient DNA repair capacity may promote telomere erosion. Accumulated single-strand breaks produced by oxidative stress have been found to be less efficiently repaired at telomeres than in the rest of the genome.28,29 Most of these studies were conducted using in vitro or in vivo experiments with highly sensitive cell lines or animals. Several studies in humans have indicated the role of DNA oxidative damage in breast tumorigenesis. Plasma malondialdehyde (MDA) was found elevated in breast cancer cases relative to the level in healthy controls30–32 and the levels of MDA-DNA adducts and 8-oxodG were also significantly higher in breast cancer cases than in controls.33–36 However, there is a lack of population-based evidence to link both telomere length and oxidative damage to the development of breast cancer. Using data from the population-based Long Island Breast Cancer Study Project (LIBCSP), we previously reported that dietary antioxidant intake was inversely associated with breast cancer risk,37 and among a smaller subset of the LIBCSP participants, the urinary oxidative damage biomarker – 15-F2-isoprostanes (15-F2t-IsoP) appeared to be positively associated with risk, although our estimates were unstable due to the small sample size.38 In the present study, we now examine whether breast cancer risk is associated with WBC telomere length, and we re-evaluate the association with the urinary oxidative damage biomarkers, but this time among a much larger sample of women from the LIBCSP. We then explore whether oxidative damage markers or dietary antioxidant intake modify the association between telomere length and breast cancer risk.