Breast Cancer Research and Treatment

, Volume 141, Issue 2, pp 307–316 | Cite as

Plasma florescent oxidation products and breast cancer risk: repeated measures in the Nurses’ Health Study

  • Renée T. FortnerEmail author
  • Shelley S. Tworoger
  • Tianying Wu
  • A. Heather Eliassen


Reactive oxygen species (ROS), normally generated through biologic processes, may damage DNA, lipids, and proteins. ROS are balanced through enzymatic mechanisms and exogenous antioxidants; imbalance results in oxidative stress. Limited data suggest an association between oxidative stress and breast cancer. We evaluated pre-diagnostic plasma fluorescent oxidation products (FlOP), a global biomarker of oxidative stress, and breast cancer risk in a nested case–control study in the Nurses’ Health Study. Participants provided two blood samples (1989–1990 and 2000–2002) (N = 18,743). 377 women developed breast cancer between the second collection and June 1, 2006. Cases were matched to 377 controls. Relative fluorescent intensity at three different excitation/emission wavelengths (FlOP_360, FlOP_320, FlOP_400) were quantified in both samples, providing distant (≥10 years before diagnosis) and proximate (≤6 years before diagnosis) measures of oxidative stress. We observed no association between FlOP and breast cancer risk in proximate or distant samples (e.g., proximate extreme quartiles: FlOP_360, RR 0.8, 95 % CI 0.5–1.3, p trend = 0.49; FlOP_320, RR 1.1, 95 % CI 0.7–1.7, p trend = 0.53; FlOP_400, RR 1.3, 95 % CI 0.8–2.0, p trend = 0.80). In general no association was observed when cross-classifying or averaging proximate and distant exposure (e.g., extreme quartile of averages: FlOP_360, OR 0.9, 95 % CI 0.6–1.4, p trend = 0.82; FlOP_400, OR 0.9, 95 % CI 0.6–1.4, p trend = 0.55), with the exception of a significant trend for average FlOP_320 (extreme quartiles, OR 1.6, 95 % CI 1.0–2.4, p trend = 0.02). We did not observe important associations between FlOP and breast cancer risk in this large prospective study, though our data suggest women with consistently high FlOP_320 may be at increased risk.


Oxidative stress Breast cancer Fluorescent oxidation products 



The authors would like to thank Susan Hankinson, Sc.D. for her important contributions to this manuscript. This work was funded by National Institute of Health Grants R01 CA131218, P01 CA87969, R01 CA49449. RT Fortner is supported in part by T32 CA09001. We would like to thank the participants and staff of the Nurses’ Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for analyses and interpretation of these data.

Conflict of interest

The authors declare no conflicts of interest.


  1. 1.
    Valko M, Leibfritz D, Moncol J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84Google Scholar
  2. 2.
    Valko M, Izakovic M, Mazur M et al (2004) Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 266:37–56PubMedCrossRefGoogle Scholar
  3. 3.
    Yager JD (2000) Endogenous estrogens as carcinogens through metabolic activation. J Natl Cancer Inst Monographs 27:67–73Google Scholar
  4. 4.
    Brooks PJ (1997) DNA damage, DNA repair, and alcohol toxicity—a review. Alcohol Clin Exp Res 21:1073–1082PubMedGoogle Scholar
  5. 5.
    Sies H (1997) Oxidative stress: oxidants and antioxidants. Exp Physiol 82:291–295PubMedGoogle Scholar
  6. 6.
    Dreher D, Junod AF (1996) Role of oxygen free radicals in cancer development. Eur J Cancer 32A:30–38PubMedCrossRefGoogle Scholar
  7. 7.
    Halliwell B (2007) Oxidative stress and cancer: have we moved forward? Biochem J 401:1. doi: 10.1042/BJ20061131 PubMedCrossRefGoogle Scholar
  8. 8.
    Kryston TB, Georgiev AB, Pissis P, Georgakilas AG (2011) Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res 711:193–201. doi: 10.1016/j.mrfmmm.2010.12.016 PubMedCrossRefGoogle Scholar
  9. 9.
    Klaunig JE, Kamendulis LM (2004) The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 44:239–267. doi: 10.1146/annurev.pharmtox.44.101802.121851 PubMedCrossRefGoogle Scholar
  10. 10.
    Ronckers CM, Erdmann CA, Land CE (2005) Radiation and breast cancer: a review of current evidence. Breast Cancer Res 7:21–32. doi: 10.1186/bcr970 PubMedCrossRefGoogle Scholar
  11. 11.
    Key TJ, Verkasalo PK, Banks E (2001) Epidemiology of breast cancer. Lancet Oncol 2:133–140. doi: 10.1016/S1470-2045(00)00254-0 PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang X, Tworoger SS, Eliassen AH, Hankinson SE (2013) Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up. Breast Cancer Res Treat 137:883–892. doi: 10.1007/s10549-012-2391-z PubMedCrossRefGoogle Scholar
  13. 13.
    Chen WY, Rosner B, Hankinson SE et al (2011) Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA 306:1884–1890. doi: 10.1001/jama.2011.1590 PubMedCrossRefGoogle Scholar
  14. 14.
    Eliassen AH, Hendrickson SJ, Brinton LA et al (2012) Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies. J Natl Cancer Inst 104:1905–1916. doi: 10.1093/jnci/djs461 PubMedCrossRefGoogle Scholar
  15. 15.
    Aune D, Chan DSM, Vieira AR et al (2012) Dietary compared with blood concentrations of carotenoids and breast cancer risk: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr 96:356–373. doi: 10.3945/ajcn.112.034165 PubMedCrossRefGoogle Scholar
  16. 16.
    Lee K-H, Shu X-O, Gao Y-T et al (2010) Breast cancer and urinary biomarkers of polycyclic aromatic hydrocarbon and oxidative stress in the Shanghai Women’s Health Study. Cancer Epidemiol Biomarkers Prev 19:877–883. doi: 10.1158/1055-9965.EPI-09-1098 PubMedCrossRefGoogle Scholar
  17. 17.
    Dai Q, Gao YT, Shu XO et al (2009) Oxidative stress, obesity, and breast cancer risk: results from the Shanghai Women’s Health Study. J Clin Oncol 27:2482–2488. doi: 10.1200/JCO.2008.19.7970 PubMedCrossRefGoogle Scholar
  18. 18.
    Khanzode SS, Muddeshwar MG, Khanzode SD, Dakhale GN (2004) Antioxidant enzymes and lipid peroxidation in different stages of breast cancer. Free Radic Res 38:81–85PubMedCrossRefGoogle Scholar
  19. 19.
    Sener DE, Gönenç A, Akinci M, Torun M (2007) Lipid peroxidation and total antioxidant status in patients with breast cancer. Cell Biochem Funct 25:377–382. doi: 10.1002/cbf.1308 PubMedCrossRefGoogle Scholar
  20. 20.
    Huang YL, Sheu JY, Lin TH (1999) Association between oxidative stress and changes of trace elements in patients with breast cancer. Clin Biochem 32:131–136PubMedCrossRefGoogle Scholar
  21. 21.
    Gönenç A, Ozkan Y, Torun M, Simşek B (2001) Plasma malondialdehyde (MDA) levels in breast and lung cancer patients. J Clin Pharm Ther 26:141–144PubMedCrossRefGoogle Scholar
  22. 22.
    Akbulut H, Akbulut KG, Icli F, Büyükcelik A (2003) Daily variations of plasma malondialdehyde levels in patients with early breast cancer. Cancer Detect Prev 27:122–126PubMedCrossRefGoogle Scholar
  23. 23.
    Polat MF, Taysi S, Gul M et al (2002) Oxidant/antioxidant status in blood of patients with malignant breast tumour and benign breast disease. Cell Biochem Funct 20:327–331. doi: 10.1002/cbf.980 PubMedCrossRefGoogle Scholar
  24. 24.
    Ray G, Batra S, Shukla NK et al (2000) Lipid peroxidation, free radical production and antioxidant status in breast cancer. Breast Cancer Res Treat 59:163–170PubMedCrossRefGoogle Scholar
  25. 25.
    Rossner P (2006) Relationship between urinary 15-F2t-isoprostane and 8-oxodeoxyguanosine levels and breast cancer risk. Cancer Epidemiol Biomarkers Prev 15:639–644. doi: 10.1158/1055-9965.EPI-05-0554 PubMedCrossRefGoogle Scholar
  26. 26.
    Tas F, Hansel H, Belce A et al (2005) Oxidative stress in breast cancer. Med Oncol 22:11–15. doi: 10.1385/MO:22:1:011 PubMedCrossRefGoogle Scholar
  27. 27.
    Wu T, Rifai N, Willett WC, Rimm EB (2007) Plasma fluorescent oxidation products: independent predictors of coronary heart disease in men. Am J Epidemiol 166:544–551. doi: 10.1093/aje/kwm120 PubMedCrossRefGoogle Scholar
  28. 28.
    Jensen MK, Wang Y, Rimm EB, Townsend MK, Willet W, Wu T (2013) Fluorescent oxidation products and risk of coronary heart disease: a prospective study in women. J American Heart Assoc (in press)Google Scholar
  29. 29.
    Wu T, Willett WC, Rifai N, Rimm EB (2007) Plasma fluorescent oxidation products as potential markers of oxidative stress for epidemiologic studies. Am J Epidemiol 166:552–560. doi: 10.1093/aje/kwm119 PubMedCrossRefGoogle Scholar
  30. 30.
    Belanger CF, Hennekens CH, Rosner B, Speizer FE (1978) The nurses’ health study. Am J Nurs 78:1039–1040PubMedGoogle Scholar
  31. 31.
    Colditz GA, Hankinson SE (2005) The Nurses’ Health Study: lifestyle and health among women. Nat Rev Cancer 5:388–396. doi: 10.1038/nrc1608 PubMedCrossRefGoogle Scholar
  32. 32.
    Hankinson SE, Willett WC, Manson JE et al (1998) Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 90:1292–1299. doi: 10.1093/jnci/90.17.1292 PubMedCrossRefGoogle Scholar
  33. 33.
    Wu T, Rifai N, Roberts LJ et al (2004) Stability of measurements of biomarkers of oxidative stress in blood over 36 hours. Cancer Epidemiol Biomarkers Prev 13:1399–1402PubMedCrossRefGoogle Scholar
  34. 34.
    Frankel EN, Neff WE, Brooks DD, Fujimoto K (1987) Fluorescence formation from the interaction of DNA with lipid oxidation degradation products. Biochim Biophys Acta 919:239–244PubMedCrossRefGoogle Scholar
  35. 35.
    Fujimoto K, Neff WE, Frankel EN (1984) The reaction of DNA with lipid oxidation products, metals and reducing agents. Biochim Biophys Acta 795:100–107PubMedCrossRefGoogle Scholar
  36. 36.
    Flynn TP, Allen DW, Johnson GJ, White JG (1983) Oxidant damage of the lipids and proteins of the erythrocyte membranes in unstable hemoglobin disease. Evidence for the role of lipid peroxidation. J Clin Investig 71:1215–1223PubMedCrossRefGoogle Scholar
  37. 37.
    El-Sohemy A, Baylin A, Kabagambe E et al (2002) Individual carotenoid concentrations in adipose tissue and plasma as biomarkers of dietary intake. Am J Clin Nutr 76:172–179PubMedGoogle Scholar
  38. 38.
    Rosner B, Cook N, Portman R et al (2008) Determination of blood pressure percentiles in normal-weight children: some methodological issues. Am J Epidemiol 167:653–666. doi: 10.1093/aje/kwm348 PubMedCrossRefGoogle Scholar
  39. 39.
    Rosner B (1983) Percentage points for a generalized ESD many-outlier procedure. Technometrics 25:165–172Google Scholar
  40. 40.
    Keaney JF, Larson MG, Vasan RS et al (2003) Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arterioscler Thromb Vasc Biol 23:434–439. doi: 10.1161/01.ATV.0000058402.34138.11 PubMedCrossRefGoogle Scholar
  41. 41.
    Basu S (2008) F2-isoprostanes in human health and diseases: from molecular mechanisms to clinical implications. Antioxid Redox Signal 10:1405–1434. doi: 10.1089/ars.2007.1956 PubMedCrossRefGoogle Scholar
  42. 42.
    Prázný M, Skrha J, Hilgertová J (1999) Plasma malondialdehyde and obesity: is there a relationship? Clin Chem Lab Med 37:1129–1130. doi: 10.1515/CCLM.1999.164 PubMedCrossRefGoogle Scholar
  43. 43.
    Byrne C, Divekar SD, Storchan GB et al (2013) Metals and breast cancer. J Mammary Gland Biol Neoplasia 18:63–73. doi: 10.1007/s10911-013-9273-9 PubMedCrossRefGoogle Scholar
  44. 44.
    Martin MB, Reiter R, Pham T et al (2003) Estrogen-like activity of metals in MCF-7 breast cancer cells. Endocrinology 144:2425–2436PubMedCrossRefGoogle Scholar
  45. 45.
    Ionescu JG, Novotny J, Stejskal V et al (2006) Increased levels of transition metals in breast cancer tissue. Neuro Endocrinol Lett 27(Suppl 1):36–39PubMedGoogle Scholar
  46. 46.
    Garcia-Morales P, Saceda M, Kenney N et al (1994) Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells. J Biol Chem 269:16896–16901PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Renée T. Fortner
    • 1
    • 2
    Email author
  • Shelley S. Tworoger
    • 1
    • 2
  • Tianying Wu
    • 3
  • A. Heather Eliassen
    • 1
    • 2
  1. 1.Channing Division of Network Medicine, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Harvard School of Public HealthBostonUSA
  3. 3.Division of Biostatistics and Epidemiology, Department of Environmental HealthUniversity of CincinnatiCincinnatiUSA

Personalised recommendations