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Carcinogenesis Advance Access originally published online on May 10, 2007
Carcinogenesis 2007 28(8):1726-1730; doi:10.1093/carcin/bgm109
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

DNA double-strand break repair capacity and risk of breast cancer

Da-Tian Bau1,2, Yi-Chien Mau1, Shian-ling Ding1,3, Pei-Ei Wu1 and Chen-Yang Shen1,4,5,*

1 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
2 Cancer Center, China Medical University Hospital, Taichung 40402, Taiwan
3 Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei 11485, Taiwan
4 Life Science Library, Academia Sinica, Taipei 11529, Taiwan
5 Graduate Institute of Environmental Science, China Medical University, Taichung 40402, Taiwan

* To whom correspondence should be addressed. Tel: +886 2 27899036; Fax: +886 2 2782 3047; Email: bmcys{at}ibms.sinica.edu.tw


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results and discussion
 Supplementary material
 References
 
A tumorigenic role of the non-homologous end-joining (NHEJ) pathway for the repair of DNA double-strand breaks (DSBs) has been suggested by our finding of a significant association between increased breast cancer risk and a cooperative effect of single-nucleotide polymorphisms in NHEJ genes. To confirm this finding, this case–control study detected both in vivo and in vitro DNA end-joining (EJ) capacities in Epstein-Barr virus-immortalized peripheral blood mononuclear cells (PBMCs) of 112 breast cancer patients and 108 healthy controls to identify individual differences in EJ capacity to repair DSB as a risk factor predisposing women to breast cancer. PBMCs from breast cancer patients consistently showed lower values of in vivo and in vitro EJ capacities than those from healthy women (P < 0.05). Logistic regression, simultaneously considering the effect of known risk factors of breast cancer, shows that the in vitro EJ capacity above the median of control subjects was associated with nearly 3-fold increased risks for breast cancer (adjusted odds ratio, 2.98; 95% confidence interval, 1.64–5.43). Furthermore, a dose–response relationship was evident between risk for breast cancer and EJ capacity, which was analyzed as a continuous variable (every unit decrease of EJ capacity being associated with an 1.09-fold increase of breast cancer risk) and was divided into tertiles based on the EJ capacity values of the controls (P for trend < 0.01). The findings support the conclusion that NHEJ may play a role in susceptibility to breast cancer.

Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; DSB, double-strand break; DTT, dithiothreitol; EJ, end joining; NHEJ, non-homologous end joining; PBMC, peripheral blood mononuclear cell; SNP, single-nucleotide polymorphism


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results and discussion
 Supplementary material
 References
 
The response of the cell to genetic injury and its ability to maintain genomic stability by means of a variety of DNA repair mechanisms are essential in preventing tumor initiation and progression. Familial cancer syndromes, including xeroderma pigmentosum and hereditary non-polyposis colorectal cancer, which are, respectively, causally linked to defective nucleotide excision repair and mismatch repair (1), emphasize the importance of DNA repair mechanisms during tumorigenesis. The fact that the family breast cancer susceptibility genes, BRCA1 and BRCA2, are involved in the homologous recombination pathway for DNA double-strand break (DSB) repair (2) supports the idea that breast cancer pathogenesis is driven by DSB-initiated chromosome instability (3), and the mechanisms involved in DNA DSB repair are of particular etiological importance during breast tumorigenesis. It is therefore intriguing that evidence for the involvement in breast cancer of the non-homologous end-joining (NHEJ) pathway, the other DSB repair pathway in mammalian cells (4–6), was provided by our findings (7) that genotypic polymorphisms of the NHEJ genes, Ku70, Ku80, DNA-PKcs, LigaseIV and XRCC4, are jointly associated with increased breast cancer risk. However, in considering whether a genotype-based finding represents a true association, the most important issue is the interpretation of the identified association. Since the genotypes analyzed in our study were mainly based on single-nucleotide polymorphisms (SNPs) located in introns which do not affect amino acid coding and therefore probably do not affect protein function, the observed associations between breast cancer risk and SNPs should be interpreted as the presence of linkage disequilibrium between these SNPs and other SNPs in exons resulting in functional polymorphisms. The critical parameter is, of course, the repair activity. To confirm this finding, this case–control study was performed using both in vivo and in vitro DNA end-joining (EJ) assays to identify individual differences in EJ capacity to repair DNA DSB as a risk factor predisposing women to breast cancer.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results and discussion
 Supplementary material
 References
 
Study participants and questionnaire
The present study included 112 female breast cancer patients and 108 age-matched healthy controls (women). All subjects gave their informed consents. All breast cancer patients had pathologically confirmed primary infiltrating ductal carcinoma of the breast. To avoid any differential recall bias of previous disease history, we deliberately randomly selected the controls from the health examination clinics of the same hospitals. A structured questionnaire was administered to both cases and controls to collect all relevant information regarding risk factors of breast cancer. Considerations regarding methodological issues in the present study (such as study design, sampling scheme, selection of the controls, validity of the questionnaire and potential bias) have been described in detail previously (7–9), and the validity of our study approach was addressed and confirmed in these studies.

Specimen collection and peripheral blood mononuclear cell line establishment
About 10 ml of peripheral blood, collected in acetate–citrate–dextrose, was obtained from each breast cancer patient before operation and from each control subject during the same time period when the samples were collected from cases. The blood samples were processed within 12–18 h of collection. Peripheral blood mononuclear cells (PBMCs), isolated as described previously (10), were cultured in RPMI-1640 containing 10% fetal calf serum. After overnight culture at a density of 1 x 106 cell/ml, Epstein-Barr virus (EBV) transformation was performed by adding 0.2 ml of virus suspension to 0.8 ml of PBMC suspension. The mixture was incubated and half the medium was changed every 3–4 days. Over a period of 2–3 weeks, EBV-transformed cell lines were established from these cases and controls and were used immediately for EJ assays without freezing and storage.

Protein extraction and quantization
To prepare protein extracts, the PBMCs were incubated for 30 min on ice in 220 mM potassium chloride, then the cell debris was removed by centrifugation at 11,000g for 15 min at 4°C, glycerol added to the protein extract to a final concentration of 10% and the extract frozen in liquid nitrogen. The protein concentration was determined using a Bio-Rad Protein Assay kit (Bio-Rad Laboratories, Hercules, CA).

In vitro functional assay of EJ capacity
To examine whether NHEJ was involved in breast cancer development, we measured EJ capacity in vitro in EBV-transformed cell lines established from the cases and controls. The assay was performed as described previously (11,12). Briefly, the cells were harvested, washed once in Dulbecco’s modified Eagle’s medium containing 10% fetal calf serum, three times in ice-cold phosphate-buffered saline and once in hypotonic lysis buffer [10 mM Tris–HCl (pH 8.0), 1 mM ethylenediaminetetraacetic acid and 5 mM dithiothreitol (DTT)], re-suspended in two volumes of hypotonic buffer, incubated for 20 min at 0°C and lysed by homogenization and then protease inhibitors (0.17 mg/ml of phenylmethylsulfonyl fluoride, 0.01 trypsin inhibitor U/ml of aprotinin, 1 µg/ml of pepstatin, 1 µg/ml of chymostatin and 1 µg/ml of leupeptin) were added. After 20 min on ice, 0.5 volumes of high-salt buffer [50 mM Tris–HCl (pH 7.5), 1 M KCl, 2 mM ethylenediaminetetraacetic acid and 2 mM DTT] was added and the extract centrifuged at 200g at 4°C for 3 h. The supernatant was then dialyzed for 3 h against 20 mM Tris–HCl (pH 8.0), 0.1 M KOAc, 20% (v/v) glycerol, 0.5 mM ethylenediaminetetraacetic acid and 1 mM DTT, snap-frozen and stored at –70°C. pBSK(+) duplex plasmid DNA (2.96 kb; Stratagene, La Jolla, CA) was linearized with EcoRI, dephosphorylated using calf intestinal phosphatase and 5'-32P end labeled using polynucleotide kinase. Cell-free extracts (50–100 µg of protein) were incubated for 5 min at 37°C before being added to the reaction mix of 50 mM triethanolamine–HCl (pH 7.5), 0.5 mM Mg(OAc)2, 60 mM KOAc, 2 mM ATP, 1 mM DTT and 100 µg/ml of bovine serum albumin containing 50 fmol of labeled linearized DNA. After incubation at 37°C for 1 h, the 32P-labeled DNA products were deproteinized for 20 min at 37°C using 500 µg/ml of proteinase K and 1% sodium dodecyl sulfate and analyzed by electrophoresis on 0.7% agarose gels. The monomer and multimer bands (substrate and products) were detected on Kodak BioMax films (Sigma Chemical Co.). The data were quantified by densitometry and, after normalization for loading and transfer, expressed as EJ efficiency calculated as intensity of EJ products/total substrate x 100%.

In vivo functional assay of EJ capacity
To examine whether NHEJ was involved in breast cancer development, we also measured EJ capacity in vivo in EBV-transformed cell lines established from the cases and controls. Briefly, plasmid pGL2 (Promega, Madison, WI) was completely linearized using either HindIII or EcoRI, as confirmed by agarose gel electrophoresis. The linearized DNA was subjected to phenol/chloroform extraction and ethanol precipitation, dissolved in sterilized water and used to transfect cells using Lipofectamine 2000 using the manufacturer’s protocol (Invitrogen). Transfectants were harvested 48 h later and assayed for luciferase activity as described previously (11).

Data analysis
The in vitro EJ capacities for the cases and controls were compared and the differences were tested by Student's t-test. The mean in vivo EJ capacities were compared using analysis of covariance, with dosage (i.e. the amount of transfected endonuclease-digested reporter gene) as a covariate for adjustment. Multivariate logistic regression analyses were used to determine the risk of developing breast cancer associated with in vitro EJ capacity, with adjustment for known risk factors for breast cancer, and multivariate-adjusted odds ratios (aORs) and their 95% confidence intervals (CIs) were estimated. EJ capacity values were analyzed as a continuous variable or partitioned in two ways. First, the median EJ capacity of control subjects was used as the cutoff value. Values above this median were considered to be normal EJ capacity, whereas values equal to or below the median were considered to be low EJ capacity. Second, a partition by tertiles was performed, where the upper tertile of the control subjects was chosen as the referent group. A set of dummy variables to represent groups with different EJ capacities was included in the logistic regression model to estimate the risk of breast cancer. To perform the linear trend test, the tertiles were recorded as 1, 2 and 3 and treated as one continuous variable in the multiple logistic regression. All P values were two-tailed.


   Results and discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
Supplementary material
 References
 
This case–control study included 112 breast cancer patients and 108 age-matched healthy controls recruited from our ongoing cohort (7,8,13,14). The risk profile of this series of study subjects was similar to that reported in our previous studies (7,8,13,14). An increased odds ratio was found to be conferred by a family history of breast cancer in female first-degree relatives (yes versus no; aOR, 1.36; 95% CI, 1.05–1.76), a younger age at menarche (≤13 versus >13 years; aOR, 1.1; 95% CI, 0.8–1.5) and had a lower frequency of a history of full-term pregnancy (no history versus having at least one full-term pregnancy; aOR, 2.5; 95% CI, 1.5–4.2). Obese women (body mass index > 24 kg/m2) showed a significantly increased odds ratio (aOR, 2.3; 95% CI, 1.3–4.1). These significant reproductive risk factors were adjusted in the later analysis.

To examine whether a reduced EJ capacity was associated with breast cancer, we measured EJ capacity in vivo and in vitro in PBMCs from cases and controls. The PBMCs collected were transformed using EBV and the EBV-immortalized PBMCs were used for further EJ assays. All blood samples were collected before any chemotherapy or radiotherapy was performed to avoid any effect of these treatments on the measurement of EJ capacity. Considerations regarding whether these assays reflect NHEJ activity have been described in detail previously (15).

The in vitro EJ capacity of the PBMCs was measured by rejoining 32P-labeled linear duplex DNA and quantifying the monomer band (substrate) and multimer bands (products) by densitometry (11,16). After normalization for loading and transferring, the EJ capacity was calculated as the intensity of the EJ product bands/intensity of all bands combined x 100% (11) (Figure 1a). The validity of this experimental approach was addressed and confirmed in our previous studies (11). In the present study, we first measured the EJ capacity using 40 µg of PBMC extract protein as a function of time and observed a linear increase in the multimer bands with increasing time of incubation up to 60 min, with no further increase (Figure 1b). Using a fixed time of 30 min, the amount of multimer bands was linearly related to the amount of cell extract protein added (Figure 1c). The EJ capacity assay was accurate and reproducible, with a coefficient of variation of 10%, confirmed by repeating 20% of the assay. We had also tested more than two independent samples from five individuals and the assays were repeated by two technicians on different people on different days, with consistent results. Furthermore, we measured the EJ capacity of the same five healthy individuals over a period of 6 months and confirmed that it is stable over this period (supplementary data are available at Carcinogenesis Online).


Figure 1
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  		Fig. 1. In vitro EJ assay to show EJ capacity in association with breast cancer. (a) In vitro EJ activity of a selected control, in which increasing amount of protein extract from her PBMCs was used. EJ activity was measured as [intensity of multimers/(multimers + monomer) x100%] by phosphoimage analysis of the gels. (b) Time course of in vitro EJ using 40 µg of PBMC extract. (c) In vitro EJ capacity of different amounts of PBMC extracts using an incubation time of 30 min. (d) In vitro EJ capacity of PBMC extracts from 112 female breast cancer patients and 108 age-matched healthy controls using 40 µg of protein and a 30 min incubation; human breast cancer cell lines BRCA1-expressing MCF-7 and HCC1937 with defective BRCA1expression were used as references.

 
The mean EJ capacity for the cases of 28.3 ± 0.6% (95% CI, 27.2–29.4) was significantly lower than that of 32.6 ± 0.6% (95% CI, 31.5–33.7) for the controls (P < 0.05) (Figure 1d). Two breast cancer cell lines, BRCA1-expressing MCF-7 cells and HCC1937 cells with defective BRCA1 expression, served as the positive and negative controls in each assay, since the genotypic status of BRCA1 is the major determinant of EJ capacity (11,12).

We then evaluated the effect of EJ capacity on breast cancer risk in three logistic regression models adjusted for known risk factors, including age, family history of breast cancer, body mass index and reproductive factors. In a logistic regression model, in which the EJ capacity was fitted as a continuous variable, the aOR of developing breast cancer was estimated, and this estimated risk was explained by both EJ capacity (which was measured as percentage) and known risk factors of breast cancer. It comes up to an aOR of 1.09 associated with EJ capacity, which means every unit decrease of EJ capacity (i.e. 1%) is associated with an 1.09-fold (95% CI, 1.04–1.14) increase of breast cancer risk (Table I). Likewise, when the EJ capacity values were dichotomized using the median EJ capacity of the control subjects, a low EJ capacity was associated with a nearly 3-fold increase in risk (aOR, 2.98; 95% CI, 1.64–5.43) (Table I). Furthermore, when the EJ capacity values were divided into tertiles based on the EJ capacity values of the controls, a dose–response relationship between decreased EJ capacity and an increased risk of breast cancer was evident (P for trend < 0.001) (Table I). We also assessed whether the EJ capacity was associated with the extent of tumor differentiation by grouping the patients according to tumor grade. Patients of any grade had a significantly lower EJ capacity than the controls, but there was no significant difference in EJ capacity between patients with different grade tumors (data not shown).


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  		Table I. Logistic regression analysis of DNA DSB EJ capacity in breast cancer patients and cancer-free control subjects

 
To measure EJ capacity in vivo, a linearized pGL2 plasmid containing the endonuclease-digested luciferase reporter gene was transfected into PBMCs, the rationale being that the luciferase gene would only be expressed after the plasmid was rejoined to form the circular form. The transfection efficiency can be normalized by ratio of the luciferase activity in cells transfected with endonuclease-digested plasmid with that in PBMCs containing the intact plasmid. The EJ capacity detected using pGL2 digested with HindIII reflects overall EJ, since this enzyme cleaves at the linker region between the promoter and the coding sequences and any EJ activity, even that resulting in small deletions or insertions, would not affect luciferase expression (Figure 2a). Since the EcoRI cutting site is in the luciferase sequence and only precise EJ can restore the original luciferase, the relative luciferase activity using this enzyme reflects precise EJ capacity (Figure 2a) (11,16). However, the methodological characteristics inherent to any in vivo assay hampered its large-scale use in this case–control study. These include differences in transfection efficiency, susceptibility to exogenous stimulation (such as transfection per se) and cellular viability between PBMCs from different individuals, all of which may affect the expression of the reporter gene, in addition to the EJ capacity. On the other hand, in our previous cell line-based study using breast epithelium (11), we demonstrated that the EJ capacity detected in vivo is consistent with, and can be predicted by, that measured in vitro. As a result, we measured the in vivo EJ capacity in PBMCs from only 22 breast cancer patients and 20 controls, selected because their cells displayed comparable transfection efficiency and viability (supplementary data are available at Carcinogenesis Online), and the results were calculated as the percentage contribution of precise EJ capacity to overall EJ capacity. The relative contribution of precise EJ to overall EJ was as important as the absolute value for precise EJ, as a higher percentage of ‘error-prone’ EJ may compete with ‘precise’ EJ, leading to illegitimate DSB repair (12). Because the amount of transfected endonuclease-digested reporter gene is also a factor determining in vivo EJ capacity, we used four different dosages for both cases and controls. Although a linear increase in the percentage contribution of in vivo precise EJ capacity to overall EJ capacity with increasing amount of digested reporter gene transfected was not observed, PBMCs from breast cancer patients consistently showed lower values than those from healthy women at all dosages examined (P < 0.05) (Figure 2b).


Figure 2
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  		Fig. 2. In vivo EJ assay to show EJ capacity in association with breast cancer. (a) The pGL2-control plasmid contains two unique restriction sites, HindIII and EcoRI, which were used for measuring overall and precise EJ capacities, respectively. (b) The percentage contribution of precise NHEJ to total NHEJ was calculated by comparing the luciferase activity expressed in PBMCs (transfected with EcoRI-digested DNA with that of the intact plasmid) divided by the luciferase activity expressed in the same PBMCs (transfected with HindIII-digested DNA with that of the intact plasmid). The results shown are the mean ±SEM for three independent transformations of PBMCs from 22 breast cancer cases and 20 controls.

 
These data are consistent with the hypothesis that NHEJ activity, reflected by the in vivo and in vitro EJ capacity, is a constitutional or host factor of breast cancer development and that breast cancer risk is highly associated with decreased EJ capacity. The present study is the first to examine the breast tumorigenic contribution of NHEJ activity, both in vitro and in vivo, and, since the EJ capacity was measured in PBMCs collected from breast cancer patients and healthy women, the results are of more biological relevance than those of previous studies on embryonic fibroblasts and breast cancer cell lines (11,17).

The study might have some potential limitations. First, the EJ capacity of mononuclear cells (the cells on which our measurements were made) may differ from the EJ capacity of the breast epithelium. Second, we cannot totally exclude the possibility that the disease state might influence EJ capacity. However, studies of the function of the familial breast cancer susceptibility genes, BRCA1 and BRCA2, provide supporting evidence that a causal link between impaired DSB repair activity, including NHEJ, and the development of breast cancer is mechanistically plausible. In addition, previous studies by ourselves (11,12) and others (17) have shown that the NHEJ capacity of breast cancer cell lines is modified by the BRCA1 genotype status of the cells, which is consistent with the notion that the EJ capacity, as a genetic trait, can be measured in any type of tissue. The lack of an association between EJ capacity and tumor grade also shows that NHEJ activity measured in PBMCs was not affected by tumor differentiation status.

Since NHEJ activity was measured by both in vitro and in vivo EJ capacity assays using freshly EBV-immortalized PBMCs in batches with both cases and controls being tested simultaneously, the possibility of confounding effects due to freezing or storage conditions or blastogenic responses after mitogen stimulation to reactivate the cells for assay, as performed in previous phenotype-based studies (18,19), can be excluded. More importantly, an equal amount of protein extract from the PBMCs from each study participant was used in our in vitro EJ assay and no DSB-forming agents were used, thus ensuring that the measured in vitro EJ capacity truly reflected the inherent NHEJ activity by avoiding any effect of individual differences in reactivity/inducibility in response to DNA damage. Finally, the use of the same restriction enzyme (EcoRI) for the preparation of the linear duplex DNA fragment (in vitro EJ assay) and the linearized plasmid (in vivo precise EJ assay) ensured that the same repair machinery was recruited and that the in vivo and in vitro results were comparable, supporting the reliability of our findings. It is important that the form of DNA DSB is an important determinant of the EJ capacity measured, and thus the EJ capacity to rejoin the DSB ends generated by EcoRI digestion detected in the present study might reflect only one subpathway of NHEJ in cells. In addition, DSBs generated by environmental insults such as ionizing radiation may not be directly rejoined, and may require additional steps in the repair pathways. However, it is worthy to emphasize that this study was more concerned about the EJ capacity to precisely repair DSB, because it is of particular importance in preventing cancer formation. This is why we were more interested in, and specifically measured, the repair of DSB ends with overhangs generated by restriction endonuclease digestion in our in vitro and in vivo assays, as correct repair of this form of DSB ends is more likely to reflect precise EJ.

The strength of our phenotypic approach is that it yields a more comprehensive estimate of the total NHEJ capacity of each individual and its impact on breast cancer risk. In other words, our study measured global levels of NHEJ rather than a specific enzymatic step in the repair process. The advantage of this approach is becoming more obvious, since new NHEJ genes, including Artemis and Cernunnos-XLF (20–22), have been discovered recently and others have still to be defined, so the simultaneous genotyping of all genes involved in NHEJ for risk prediction is not practical. This phenotype-based study of NHEJ activity and our genotype-based study of genotypic polymorphisms of the NHEJ genes (7), both of which were found to be associated with breast cancer risk, provide essential support for the tumorigenic contribution of NHEJ during breast cancer formation. This suggestion is further supported by the functional interaction between NHEJ activity and the breast cancer susceptibility genes, ATM, Chk2 and BRCA1 (11,12). The findings of the present study are important not only in providing clues to understanding how breast cancer develops but are also of clinical relevance. A variety of antitumor therapies and drugs depends on their ability to cause DSB formation in tumor cells, subsequently resulting in cell death, thus the EJ capacity measured in the present study may also serve as an important indicator for determining the choice of anticancer drug targets and therapeutic and diagnostic approaches.


   Supplementary material
Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Supplementary material
References
 
Supplementary data can be found at http://carcin.oxfordjournals.org/


   Acknowledgments
 
Conflict of Interest statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Supplementary material
 References
 

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Received December 29, 2006; revised April 24, 2007; accepted April 30, 2007.


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