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[Cancer Research 65, 1105-1111, February 1, 2005]
© 2005 American Association for Cancer Research

Epidemiology and Prevention

Polymorphisms in Genes Related to Oxidative Stress (MPO, MnSOD, CAT) and Survival After Treatment for Breast Cancer

Christine B. Ambrosone1, Jiyoung Ahn1,4, Keshav K. Singh2, Hamed Rezaishiraz3, Helena Furberg5, Carol Sweeney6, Brian Coles7 and Andrew Trovato8

Departments of 1 Epidemiology, 2 Cancer Genetics, and 3 Health Behaviors, Roswell Park Cancer Institute, Buffalo, New York; 4 Division of Nutritional Sciences, Cornell University, Ithaca, New York; 5 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 6 Department of Family and Preventive Medicine, Health Research Center, Salt Lake City, Utah; 7 Division of Molecular Epidemiology, National Center for Toxicological Research, Jefferson, Arkansas; and8 Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York

Requests for reprints: Christine B. Ambrosone, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-3082; Fax: 716-845-8487; E-mail: christine.ambrosone{at}roswellpark.org.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The proximate cause of cancer cell death by radiation therapy and a number of therapeutic agents is through generation of reactive oxygen species, resulting in DNA damage as well as mitochondrial membrane disruption, triggering the apoptotic cascade. Because mitochondrial manganese superoxide dismutase catalyzes conversion of superoxide radicals to H2O2, with catalase neutralizing H2O2 and myeloperoxidase converting H2O2 to highly reactive hypochlorous acid, we hypothesized that gene variants could impact the efficacy of treatment for breast cancer and improve survival. Women who were treated with radiation and/or chemotherapy for incident breast cancer at the Arkansas Cancer Research Center from 1985 to 1996 were identified. DNA was extracted from paraffin-embedded normal tissue (n = 279), and MnSOD, CAT, and MPO genotypes were determined using mass spectrometry. Cox proportional hazards models were adjusted for age, race, stage with node status, and estrogen receptor and progesterone receptor status. Women who were homozygous for MPO G alleles, associated with increased transcription, had better survival (hazard ratio, 0.60; 95% confidence interval, 0.38-0.95; P = 0.03) than those with common alleles. Both CAT TT and MnSOD CC genotypes were associated with nonsignificant reduced hazard of death. When we combined genotypes associated with higher levels of reactive oxygen species for MnSOD and MPO, women with MnSOD CC and MPO GG genotypes had a 3-fold decrease in hazard of death (hazard ratio, 0.33; 95% confidence interval, 0.13-0.80; P = 0.01). These data indicate that gene variants that impact oxidative stress modify prognosis after treatment for breast cancer.

Key Words: breast cancer • survival • reactive oxygen species • polymorphism


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Radiation therapy and a number of chemotherapeutic agents, particularly anthracyclines, exert their antitumor effects through increased formation of reactive oxygen species (ROS), including hydroxyl radicals (OH), hydrogen peroxide (H2O2), and superoxide anions (O2; refs. 1–3). Oxidative stress provokes cell death as a result of massive cellular damage associated with lipid peroxidation and alterations of proteins and nucleic acids (4), triggering apoptosis through the mitochondria (5). Anticancer agents and radiation therapy can cause mitochondrial permeabilization through enhanced generation of ROS, and once the mitochondrial membrane barrier function is lost, several other factors contribute to cell death (5).

Whereas ROS, among other factors, induce or facilitate mitochondrial permeabilization, glutathione and antioxidant enzymes such as manganese superoxide dismutase (MnSOD) and catalase (CAT) inhibit it (6). These enzymes form the first line of defense against superoxide and hydrogen peroxide. MnSOD, which is induced with free radical challenge (7), is synthesized in the cytosol and posttranscriptionally modified for transport into the mitochondrion (8, 9). In the mitochondrion, MnSOD catalyzes the dismutation of two superoxide radicals, producing H2O2 and oxygen. Catalase is a heme enzyme that has a predominant role in controlling hydrogen peroxide concentration in human cells, by converting H2O2 into H2O and O2. With superoxide dismutase (SOD) and glutathione peroxidase, catalase constitutes a primary defense against oxidative stress and may provide resistance to the effects of radiation and chemotherapy. Indeed, chronic exposure of fibroblasts to increasing concentrations of H2O2 and O2 results in development of a stable oxidative stress–resistant phenotype characterized by increased cellular antioxidants including glutathione peroxidase, SOD, and catalase (10). H2O2, if not neutralized, may contribute to further generation of ROS by a reaction catalyzed by myeloperoxidase (MPO). MPO generates ROS endogenously by functioning as an antimicrobial enzyme, catalyzing a reaction between H2O2 and chloride to generate hypochlorous acid, a potent oxidizing agent. Hypochlorous acid further reacts with other biological molecules to generate secondary radicals (11). Thus, ultimate levels of potentially cytotoxic ROS may depend, in part, upon the balance between activities of MnSOD, catalase, and MPO, determining further generation of ROS or detoxification of H2O2 (Fig. 1).



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  		Figure 1. Enzymes related to generation of and reduction of ROS and hypothesized alleles for better survival. HOCL, hypochlorous acid; GPX, glutathione peroxidase.

 
Activity levels of these enzymes are likely affected by functional polymorphisms in the genes encoding them. A polymorphism in MnSOD exists in codon 16, which is located at position –9 of the mature protein and results in the incorporation of either alanine (C allele) or valine (T allele) in the mitochondrial targeting sequence. Recent experimental data indicate that the Ala-containing MnSOD is targeted into the mitochondria, whereas the Val form of the protein is partially arrested in the inner mitochondrial membrane (12). Whereas one would intuitively hypothesize that the less efficient form (T) would be associated with higher levels of ROS and greater risk of cancer, it is the C polymorphism that has been associated with risk of breast (13, 14), prostate (15), and bladder (16), but not lung (17) cancer. This increased risk with C alleles might be due to other mechanisms, such as protein-protein interactions, and subsequent disruption of MnSOD despite efficient localization to the mitochondrion. The Ala9Val polymorphism has been evaluated in one small study of radiotherapy (18), with null findings. A frequently occurring single nucleotide polymorphism in the promoter region of the MPO gene is a –463 G->A substitution, which is located in the consensus binding site of an SP1 transcription factor in the 5' upstream region of the gene (19). The MPO A variant allele confers lower transcriptional activation than the –463 G common allele in vitro due to disruption of the binding site (20), and the G allele has been associated with increased MPO mRNA and protein levels in myeloid leukemia cells (21). The A allele, presumed associated with lower levels of ROS, has been associated with decreased lung cancer risk in several (22–26), but not all studies (27, 28), as well as decreased risk of Alzheimer's disease (29). We recently found decreased risk of breast cancer among women with A alleles (30). For catalase, a common polymorphism has been identified in the promoter region of the CAT gene, a –262 C->T substitution on the 5' region of the human CAT gene from the transcription start site (31). The variant alters gene expression when incorporated upstream in a Luciferase reporter construct and transiently transfected in HepG2 (human liver) cells and K562 (human blood cells). Different patterns have also been detected on gel shift analysis (31), and we have found that the T allele is associated with lower levels of red blood cell catalase activity.9 This variability in catalase activity is thought to play a role in host response to oxidative stress and, indeed, variant CAT alleles seemed to be associated with increased risk of hypertension (32) and arsenic-induced hyperkeratosis (33), conditions likely related to oxidative stress. As illustrated in Fig. 1, we hypothesized that polymorphisms in MnSOD, MPO, and CAT that were likely to result in higher levels of oxidative stress would be associated with greater cytotoxicity and, thereby, better survival in women receiving radiation and chemotherapy for breast cancer.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
This study was conducted at the University of Arkansas for Medical Sciences under a protocol approved by the Institutional Review Board, and the methods have been previously described (34, 35). Briefly, we identified eligible patients through the Arkansas Cancer Research Center (ACRC) Tumor Registry, and obtained information on demographic, pathologic, and clinical variables. The ACRC Registry actively conducts annual follow-up for each patient, contacting the physician or the patient, and maintains information on date last contacted, vital status, and recurrence status. Most patients had been followed up by the registry within 2 years of the date that registry records were queried for our study. There were only six living women with last contact dates more than 2 years before the end of the study. Eligibility criteria included diagnosis with incident, primary breast cancer and treatment with chemotherapy and/or radiation therapy. The majority of women who received chemotherapy were treated with cytoxan (95%), most frequently in combination with methotrexate, Adriamycin (76%), or 4-fluorouracil. Normal, paraffin-embedded lymph node tissue from surgery was obtained from pathology archives for DNA extraction; for women with no nodes available, skin or other tissue was used. DNA was extracted from tissue blocks as previously described (34) and polymorphisms for MnSOD, MPO, and CAT were assessed using Sequenom's high-throughput, matrix-assisted laser desorption ionization-time of flight mass spectrometry (36). PCR was done for MnSOD using primers 5'-ACGTTGGATGCTGTGCTTTCTCGTCTTCAG-3' and 5'-ACGTTGGATGTTCTGCCTGGAGCCCAGATAC-3', for MPO using primers 5'-ACGTTGGATGTCTTGGGCTGGTAGTGC-3' and 5'-TGGATGTATTTTTAGTAGATACAGGGTTTCA-3', and for CAT using primers 5'-ACGTTGGATGTCTGGCCCAGCAATTGGAGAG-3' and 5'-ACGTTGGATGAGGATGCTGATAACCGGGAG-3'. Controls for each genotype were included on each plate as well as two NTC controls per plate, and laboratory staff were blinded to case/control status.

We first evaluated relationships between patient and tumor characteristics by genotype using Pearson's {chi}2 test. Crude associations between genotypes for MnSOD, MPO, and CAT and overall survival were evaluated using Kaplan-Meier survival function. Survival time was calculated as the time from diagnosis to death or to the last contact date for living subjects. Person-years were calculated as the sum of survival times for all subjects within a group. Because a small proportion of women died from noncancer (n = 6) or unknown (n = 19) causes, we also conducted analysis including only those who died from known cancer. Both heterozygotes and homozygotes were assessed separately in relation to the referent. Because hazard ratios (HR) for heterozygotes were close to unity for all genotypes, heterozygotes were combined with homozygotes as the referent categories to stabilize risk estimates. Cox proportional hazard models were constructed to assess potential confounding effects of other breast cancer prognostic factors, including age, ethnicity, stage with nodal status, and estrogen and progesterone receptor status. The final multivariate-adjusted models shown include those factors that either changed the estimated effect by 10% or more in a best-fitting model, which was developed by starting with a full model and then excluding covariates that did not improve the overall fit. To examine the joint effects of genotypes, we created dummy variables, combining genotypes for MnSOD and MPO, MnSOD and CAT, and MPO and CAT. Analyses were conducted using SAS version 8.2.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Population Characteristics. Characteristics of the study population are shown in Table 1. Women were primarily Caucasian (18% African American), and there was a higher proportion of women with later-stage, node-positive, estrogen receptor–negative breast cancer than observed in many population-based studies, perhaps because the ACRC is a tertiary care facility. There were no significant differences in patient and disease characteristics by any of the genotypes (data not shown). The median follow-up time for women alive at the end of observation was 73 months; of the 279 women included in the study, there were 84 deaths.


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  		Table 1. Demographic information and pathologic characteristics of study participants and distributions of characteristics by genotype for MnSOD, MPO, and CAT (N = 279)

 
Genotypes and Risk. Associations between overall survival and specific genotypes are shown in Figs. 2, 3, and 4. As hypothesized, genotypes related to higher levels of ROS for MPO, MnSOD, and CAT were associated with better survival. Table 2 shows Cox proportional HRs for these relationships, with model 1 adjusted for age and stage at diagnosis. Although initial models were constructed controlling for age, ethnicity, stage with nodal status, estrogen and progesterone receptor status, tumor grade, and treatment, only age and stage made significant contributions to the models. Because race and estrogen/progesterone receptor status changed HRs somewhat, they are included in the fully adjusted models shown. For MnSOD, women with CC genotypes, the putative allele resulting in more efficient targeting of the mitochondrion, had better survival than those with at least one T allele (adjusted HR, 0.70; 95% CI, 0.40-1.24; P = 0.22), although the association was not significant (P = 0.22). For MPO, homozygosity for G (high activity) alleles was also associated with reduced hazard of death (HR, 0.60; 95% CI, 0.38-0.95; P = 0.03). Similar, although nonsignificant, associations were noted for CAT TT genotypes. Because H2O2 resulting from MnSOD dismutation can be reduced by catalase, and is also a substrate for MPO, generating the highly reactive hypochlorous acid, we were interested in assessing the role of combined genotypes for MPO, CAT, and MnSOD. As shown in Table 3, the combined effects of MnSOD and MPO were greater than those for either polymorphism alone. Women with MnSOD CC and MPO GG genotypes had the greatest reduced risk relative to all other genotype combinations (adjusted HR, 0.33; 95% CI = 0.13-0.80; P = 0.01). Combining genotypes for CAT and MnSOD as well as CAT and MPO was somewhat noninformative due to the small numbers of women with both genotypes, although there did seem to be a reduction in risk with the combinations of genotypes associated with better survival for CAT and both MPO and MnSOD. When analyses were limited to disease-specific mortality, relationships were similar, with stronger associations for MPO and hazard of death (adjusted HR, 0.52; 95% CI, 0.29-0.92; P = 0.02) than observed for all-cause mortality. There were no differences for MnSOD and CAT, and relationships remained nonsignificant (data not shown). When we combined genotypes and evaluated only disease-specific mortality, the reduced hazard noted for all-cause mortality remained, although the association was of borderline significance, perhaps due to the smaller sample size (adjusted HR, 0.37; 95% CI, 0.14-0.99; P = 0.05).



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  		Figure 2. Kaplan-Meier function for overall survival among women treated for breast cancer by MnSOD genotypes. Test for survival by log rank method (P = 0.34).

 


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  		Figure 3. Kaplan-Meier function for overall survival among women treated for breast cancer by MPO genotypes. Test for survival by log rank method (P = 0.07).

 


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  		Figure 4. Kaplan-Meier function for overall survival among women treated for breast cancer by CAT genotypes. Test for survival by log rank method (P = 0.15).

 

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  		Table 2. Associations between MnSOD, MPO, and CAT genetic polymorphisms and survival after treatment for breast cancer

 

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  		Table 3. Associations between MnSOD, CAT, and MPO genetic polymorphisms and survival after treatment for breast cancer

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this appraisal of the effects of polymorphisms involved in an oxidative stress mechanism on survival after treatment for breast cancer, we found that women with genotypes that would result in higher levels of ROS had better overall survival than those with genotypes associated with less generation of ROS. These results indicate that genetic variants that may result in increased oxidative stress enhance the effects of chemotherapy and/or radiation, resulting in better efficacy of treatment and, thus, better survival. Results were strongest for the high-activity MPO polymorphism, and when genotypes were combined, MnSOD variants associated with more efficient mitochondrial localization in combination with high-activity MPO alleles afforded greatly reduced hazard of death.

Due to the large body of literature on the role of the mitochondrial MnSOD in cancer cell survival, we had expected that MnSOD variants would have the greatest effect on survival after treatment for breast cancer. Experimental results indicate that MnSOD prevents the disruption of mitochondrial membrane potential (37), and inhibition of SOD causes accumulation of superoxide radicals, leading to free radical–mediated damage to mitochondrial membranes and apoptosis of cancer cells (38). In a commentary on the study of MnSOD and apoptosis of cancer cells, Cleveland and Kastan (39) suggested that a promising way of treating some cancers could be by increasing levels of ROS and inhibition of SOD. However, clinical studies of tumor levels of MnSOD and survival have been mixed. Although overexpression of MnSOD is associated with better survival of patients with esophageal and gastric cancer (40), gastric cell lines overexpressing MnSOD have shown resistance to doxorubicin (41, 42) but not to 5-fluorouracil (41). Overexpression of MnSOD in ovarian cancer cell lines also resulted in increased radioresistance (43), and in breast cancer cell lines resulted in increased resistance to Adriamycin and other oxidants (44). It is possible that MnSOD overexpression may lead to increased ROS and better tumor cell kill, or it may be protective of tumor cells, depending on the type of cells involved and the agents used. These discrepancies regarding the role of expression of MnSOD in relation to cancer prognosis remain to be clarified. In our study, we evaluated inherited genetic polymorphisms rather than tissue levels of enzymes in relation to survival, to obtain a more systemic marker of oxidant and antioxidant capabilities. Chemotherapeutic drugs are also metabolized in the liver and ROS may be neutralized in organs other than the target tissue, particularly in the blood. MPO is also found in neutrophils, so systemic capabilities are important. Genetic polymorphisms provide a marker for these systemic capabilities and provide data more extensive than levels in tumor tissue alone, which are also affected by tumor stage and grade.

To our knowledge, there have been no studies on the role of MnSOD variants in relation to survival after treatment for breast cancer; however, one small study (n = 80) of women receiving radiotherapy for breast cancer found no effects of the MnSOD polymorphisms on clinically detectable skin reactions to the therapy (18). There are fewer data regarding the potential role of catalase in treatment efficacy or cancer survival. However, there is substantial evidence that catalase plays an important role in the blocking of oxidative stress. It is possible that we did not observe associations between these genotypes and breast cancer survival because of inadequate power. With the sample size available (n = 276 for MnSOD and n = 279 for CAT), and the number of deaths (n = 81 and 83, respectively), we would only have adequate power (0.80) to be able to detect a HR of 0.57 for MnSOD and 0.42 for CAT. These HRs are much more substantial than those detected in our study, and we were clearly underpowered for MnSOD and CAT to detect smaller risk estimates.

Strongest associations were noted between polymorphisms in MPO and breast cancer survival. Although endogenous antioxidant enzymes have been evaluated in relation to treatment efficacy and chemoresistance, there has been little work on the interactions between MPO and cancer cell survival. An exception to this is the evaluation of MPO-positive blast cells as a prognostic factor for myeloid leukemia because the MPO gene is expressed in immature myeloid cells (45). The polymorphism has been studied extensively in relation to lung cancer risk, with fairly consistent findings for decreased risk with the low-activity A alleles (22–26), although not all studies are in agreement (27, 28). However, this is the first study to assess MPO variants in relation to survival. Although the greatest effects on survival seemed to be due to higher-activity MPO genotype, combined genotypes were associated with even greater risk reduction. Because MPO uses H2O2 as a substrate for the production of hypochlorous acid, as shown in Fig. 1, it is plausible that the variant associated with more efficient availability of MnSOD would enhance the effects of MPO on cancer survival. Although small sample size resulted in unstable, nonsignificant risk estimates, it seemed that CAT and MPO, as well as MnSOD and CAT genotype combinations associated with higher ROS also greatly decreased hazard of death with breast cancer, and increasing numbers of putative alleles also impacted survival.

Although these findings indicate that variability in endogenous processes that generate and protect from oxidative stress impact cancer survival, this preliminary report needs to be replicated in a larger, more homogeneous study population. Because the study population consisted of women with various disease characteristics who received several varied and repeated treatments, we are unable to determine if effects differ by therapies given, disease stage, and so forth. However, both cyclophosphamide and Adriamycin, the drugs most often used in this population, as well as radiation therapy, generate ROS, which results in massive damage to DNA and proteins, and triggers apoptotic signaling. Thus, moderation of treatment effects on survival by genetic variants in oxidative stress–related genes is likely to be more generalized and global. Because of the similar mechanisms for the varied therapies, it is likely that the this heterogeneity would have less of an impact on associations than if we were evaluating polymorphisms for enzymes involved in metabolism of specific chemotherapeutic drugs. Furthermore, adjustment of models for treatments given do not alter HRs. Although we can conclude that treatments given did not confound relationships between genotypes and survival, it is still possible that associations would be stronger for some therapeutic agents than for others. There was also heterogeneity in the study population, but we were able to model the effects of these potential clinical and demographic confounders on HRs. Only age and stage at diagnosis affected relationships, and both adjusted and unadjusted relationships are shown.

In summary, our data provide the first report that women with high-activity MPO genotypes, and to a lesser extent, CAT and MnSOD genotypes associated with higher levels of ROS, have better breast cancer survival after treatment than those with alleles that offer better protection from oxidative stress.


   Acknowledgments
 
Grant support: Arkansas Breast Cancer Research Fund.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Angie Stone for performing DNA extractions and Fred F. Kadlubar for scientific consultation.


   Footnotes
 
9 S. A. Nowell, W. Davis, J. Ahn, C. Ambrosone, unpublished data. Back

Received 6/30/04. Revised 11/12/04. Accepted 11/24/04.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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