This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ambrosone, C. B. Articles by Trovato, A. Search for Related Content PubMed PubMed Citation Articles by Ambrosone, C. B. Articles by Trovato, A.

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

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.

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

This article has been cited by other articles:

				S. A. Glynn, B. J. Boersma, T. M. Howe, H. Edvardsen, S. B. Geisler, J. E. Goodman, L. A. Ridnour, P. E. Lonning, A.-L. Borresen-Dale, B. Naume, et al. A Mitochondrial Target Sequence Polymorphism in Manganese Superoxide Dismutase Predicts Inferior Survival in Breast Cancer Patients Treated with Cyclophosphamide Clin. Cancer Res., June 15, 2009; 15(12): 4165 - 4173. [Abstract] [Full Text] [PDF]

				T. IGUCHI, S. SUGITA, C. Y. WANG, N. B. NEWMAN, T. NAKATANI, and G. P. HAAS MnSOD Genotype and Prostate Cancer Risk as a Function of NAT Genotype and Smoking Status In Vivo, January 1, 2009; 23(1): 7 - 12. [Abstract] [Full Text] [PDF]

				S.-H. Tan, S.-C. Lee, B.-C. Goh, and J. Wong Pharmacogenetics in Breast Cancer Therapy Clin. Cancer Res., December 15, 2008; 14(24): 8027 - 8041. [Abstract] [Full Text] [PDF]

				A. Bag and N. Bag Target Sequence Polymorphism of Human Manganese Superoxide Dismutase Gene and Its Association with Cancer Risk: A Review Cancer Epidemiol. Biomarkers Prev., December 1, 2008; 17(12): 3298 - 3305. [Abstract] [Full Text] [PDF]

				B. D. Lawenda, K. M. Kelly, E. J. Ladas, S. M. Sagar, A. Vickers, and J. B. Blumberg Should Supplemental Antioxidant Administration Be Avoided During Chemotherapy and Radiation Therapy? J Natl Cancer Inst, June 4, 2008; 100(11): 773 - 783. [Abstract] [Full Text] [PDF]

				J.-Y. Choi, M. L. Neuhouser, M. J. Barnett, C.-C. Hong, A. R. Kristal, M. D. Thornquist, I. B. King, G. E. Goodman, and C. B. Ambrosone Iron intake, oxidative stress-related genes (MnSOD and MPO) and prostate cancer risk in CARET cohort Carcinogenesis, May 1, 2008; 29(5): 964 - 970. [Abstract] [Full Text] [PDF]

				M. Udler, A.-T. Maia, A. Cebrian, C. Brown, D. Greenberg, M. Shah, C. Caldas, A. Dunning, D. Easton, B. Ponder, et al. Common Germline Genetic Variation in Antioxidant Defense Genes and Survival After Diagnosis of Breast Cancer J. Clin. Oncol., July 20, 2007; 25(21): 3015 - 3023. [Abstract] [Full Text] [PDF]

				J.-Y. Choi, M. L. Neuhouser, M. Barnett, M. Hudson, A. R. Kristal, M. Thornquist, I. B. King, G. E. Goodman, and C. B. Ambrosone Polymorphisms in Oxidative Stress-Related Genes Are Not Associated with Prostate Cancer Risk in Heavy Smokers Cancer Epidemiol. Biomarkers Prev., June 1, 2007; 16(6): 1115 - 1120. [Abstract] [Full Text] [PDF]

				P. J. Gillies and E. S. Krul Using Genetic Variation to Optimize Nutritional Preemption J. Nutr., January 1, 2007; 137(1): 270S - 274S. [Abstract] [Full Text] [PDF]

				J. Ahn, C. B. Ambrosone, P. A. Kanetsky, C. Tian, T. A. Lehman, S. Kropp, I. Helmbold, D. von Fournier, W. Haase, M. L. Sautter-Bihl, et al. Polymorphisms in Genes Related to Oxidative Stress (CAT, MnSOD, MPO, and eNOS) and Acute Toxicities from Radiation Therapy following Lumpectomy for Breast Cancer Clin. Cancer Res., December 1, 2006; 12(23): 7063 - 7070. [Abstract] [Full Text] [PDF]

				S. S. Wang, S. Davis, J. R. Cerhan, P. Hartge, R. K. Severson, W. Cozen, Q. Lan, R. Welch, S. J. Chanock, and N. Rothman Polymorphisms in oxidative stress genes and risk for non-Hodgkin lymphoma Carcinogenesis, September 1, 2006; 27(9): 1828 - 1834. [Abstract] [Full Text] [PDF]