Advertisement

Breast Cancer Research and Treatment

, Volume 133, Issue 3, pp 881–888 | Cite as

Differential oxidative status and immune characterization of the early and advanced stages of human breast cancer

  • C. Panis
  • V. J. Victorino
  • A. C. S. A. Herrera
  • L. F. Freitas
  • T. De Rossi
  • F. C. Campos
  • A. N. Colado Simão
  • D. S. Barbosa
  • P. Pinge-Filho
  • R. Cecchini
  • A. L. Cecchini
Preclinical Study

Abstract

Breast cancer is the malignant neoplasia with the highest incidence in women worldwide. Chronic oxidative stress and inflammation have been indicated as major mediators during carcinogenesis and cancer progression. Human studies have not considered the complexity of tumor biology during the stages of cancer advance, limiting their clinical application. The purpose of this study was to characterize systemic oxidative stress and immune response parameters in early (ED; TNM I and II) and advanced disease (AD; TNM III and IV) of patients diagnosed with infiltrative ductal carcinoma breast cancer. Oxidative stress parameters were evaluated by plasmatic lipoperoxidation, carbonyl content, thiobarbituric reactive substances (TBARS), nitric oxide levels (NO), total radical antioxidant parameter (TRAP), superoxide dismutase, and catalase activities and GSH levels. Immune evaluation was determined by TNF-α, IL-1β, IL-12, and IL-10 levels and leukocytes oxidative burst evaluation by chemiluminescence. Tissue damage analysis included heart (total CK and CKMB), liver (AST, ALT, GGT), and renal (creatinine, urea, and uric acid) plasmatic markers. C-reactive protein (CRP) and iron metabolism were also evaluated. Analysis of the results verified different oxidative stress statuses occur at distinct cancer stages. ED was characterized by reduction in catalase, 8-isoprostanes, and GSH levels, with enhanced lipid peroxidation and TBARS levels. AD exhibited more pronounced oxidative status, with reduction in catalase activity and TRAP, intense lipid peroxidation and high levels of NO, TBARs, and carbonyl content. ED patients presented a Th2 immune pattern, while AD exhibited Th1 status. CRP levels and ferritin were increased in both stages of disease. Leukocytes burst impairment was observed in both the groups. Plasma iron levels were significantly elevated in AD. The data obtained indicated that oxidative stress enhancement and immune response impairment may be necessary to ensure cancer progression to advanced stages and may result from both host and tumor inflammatory mediators.

Keywords

Breast cancer Immune response status Oxidative stress Inflammation 

Abbreviations

AD

Advanced breast cancer patients

ED

Early disease breast cancer patients

TNM

Tumor node metastasis classification

SOD

Superoxide dismutase

GSH

Reduced glutathione

TCA

Trichloric acetic acid

TRAP

Total antioxidant capacity

ABAP

2,2′azobis

RLU

Relative light unities

NO

Nitric oxide

TBARS

Thiobarbituric reactive substances

MDA

Malondialdehyde

DNPH

Dinitrophenylhydrazine

AUC

Area under the curve

LDL

Low density lipoprotein

CL

Chemiluminescence

TNF-α

Tumor necrosis factor alpha

ER

Estrogen receptors

PR

Progesterone receptors

HER-2

Human epidermal growth factor receptor

CAT

Catalase

GSH

Reduced glutathione

AST

Aspartate aminotransferase

ALT

Alanine aminotransferase

GGT

Gamma glutamyl transpeptidase

CK

Creatine kinase

CKMB

Creatine kinase MB fraction

URCA

Uric acid levels

IL-1

Interleukin 1

IL-6

Interleukin 6

IL-12

Interleukin 12

IL-10

Interleukin 10

Notes

Acknowledgments

The authors are grateful to Jesus Vargas for his exceptional technical assistance and the Fundação Araucária, CNPq and CAPES for providing financial support.

Conflict of interest

The authors declare there are no conflicts of interest.

References

  1. 1.
    Boyle P, Howell A (2010) The globalization of breast cancer. Breast Cancer Res 12(Suppl 4):S7PubMedCrossRefGoogle Scholar
  2. 2.
    Howell A (2010) The emerging breast cancer epidemic: early diagnosis and treatment. Breast Cancer Res 12(Suupl 4):S10PubMedCrossRefGoogle Scholar
  3. 3.
    Gago-Dominguez M, Jiang X, Castelao E (2007) Lipid peroxidation, oxidative stress genes and dietary factors in breast cancer protection: a hypothesis. Breast Cancer Res 9:201PubMedCrossRefGoogle Scholar
  4. 4.
    Bae YJ, Yeon JY, Sung CJ, Kim HS, Sumg MK (2009) Dietary intake and serum levels of iron in relation to oxidative stress in breast cancer patients. J Clin Biochem Nutr 45:355–360PubMedCrossRefGoogle Scholar
  5. 5.
    Tas F, Hansel H, Belce A, Ilvan F, Argon A, Camlica H, Topuz E (2005) Oxidative stress in breast cancer. Med Oncol 22(1):11–15PubMedCrossRefGoogle Scholar
  6. 6.
    Wang M, Dhingra K, Hittelman WN, Liehr JG, De Andrade M, Li D (1996) Lipid peroxidation-induced putative malondialdehyde-DNA adducts in human breast tissues. Cancer Epidemiol Biom Prev 5(9):705–710Google Scholar
  7. 7.
    Gonenç A, Erten D, Aslan S, Akinci M, Simsek B, Torun M (2006) Lipid peroxidation and antioxidant status in blood and tissue of malignant breast tumor and benign breast disease. Cell Biol Int 30(4):376–380PubMedCrossRefGoogle Scholar
  8. 8.
    Mannello F, Tonti GAM, Pagliarani S, Benedetti S, Canestrari F, Zhu W, Qin W, Sauter ER (2007) The 8-epimer of prostaglandin F2α, a marker of lipid peroxidation and oxidative stress, is decreased in the nipple aspirate fluid of women with breast cancer. Int J Cancer 120(9):1971–1976PubMedCrossRefGoogle Scholar
  9. 9.
    Feger F, Ferry-Dumazet H, Matsuda MM, Bordenave J, Dupouy M, Nussler AK, Arock M, Devevey L, Nafziger J, Guilosson JJ, Reiffers J, Mossalayi MD (2001) Role of iron in tumor cell protection from the pro-apoptotic effect of nitric oxide. Cancer Res 61:5289–5294PubMedGoogle Scholar
  10. 10.
    Kohgo Y, Ikuta K, Ohtake T, Torimoto Y, Kato J (2008) Body iron metabolism and pathophysiology of iron overload. Int J Hematol 88:7–15PubMedCrossRefGoogle Scholar
  11. 11.
    Mannello F, Tonti GA, Simone P, Ligi D, Medda V (2011) Iron-binding proteins and C-reactive protein in nipple aspirate fluids: role of iron-driven inflammation in breast cancer environment? Am J Transl Res 3(1):100–113Google Scholar
  12. 12.
    DeNardo DG, Coussens LM (2007) Inflammation and breast cancer. Balancing immune response: crosstalk between adaptative and innate immune cells during breast cancer progression. Breast Cancer Res 9:212PubMedCrossRefGoogle Scholar
  13. 13.
    Repetto M, Reides C, Carretero MLG, Costa M, Griemberg G, Llesuy S (1996) Oxidative stress in blood of HIV infected patients. Clin Chim Acta 225:107–117CrossRefGoogle Scholar
  14. 14.
    Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126PubMedCrossRefGoogle Scholar
  15. 15.
    Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474PubMedCrossRefGoogle Scholar
  16. 16.
    Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205PubMedCrossRefGoogle Scholar
  17. 17.
    Gonzales-Flecha B, Llesuy S, Boveris A (1991) Hydroperoxide-initiated chemiluminescence: an assay for oxidative stress in biopsies of heart, liver and muscle. Free Rad Biol Med 10:93–100CrossRefGoogle Scholar
  18. 18.
    Panis C, Mazzuco TL, Costa CZF, Victorino VJ, Tatakihara VLH, Yamauchi LM, Yamada-Ogatta SF, Cecchini R, Pinge-Filho P (2011) Trypanosoma cruzi: effect of the absence of 5-lipoxygenase (5-LO)-derived leukotrienes on levels of cytokines, nitric oxide and iNOS expression in cardiac tissue in the acute phase of infection in mice. Exp Parasitol 127:58–65PubMedCrossRefGoogle Scholar
  19. 19.
    Oliveira JA, Cecchini R (2000) Oxidative stress of liver in hamsters infected with Leishmania (L.) chagasic. J Parasitol 86(5):1067–1072PubMedCrossRefGoogle Scholar
  20. 20.
    Panis C, Herrera AC, Victorino VJ, Campos FC, Freitas LF, De Rossi T, Colado Simão AN, Cecchini AL, Cecchini R. Oxidative stress and hematological profiles of advanced breast cancer patients subjected to paclitaxel or doxorubicin chemotherapy. Breast Cancer Res Treat. 2011 Aug 3. [Epub ahead of print]Google Scholar
  21. 21.
    Miller GL (1959) Protein determination for large numbers of samples. Anal Chem 31:964CrossRefGoogle Scholar
  22. 22.
    Kukovetz EM, Bratschitcch G, Hofer HP, Egger G, Schaur RJ (1997) Influence of age on the release of reactive oxygen species by phagocytes as measured by a whole blood chemiluminescence assay. Free Rad Biol Med 22(3):433–438PubMedCrossRefGoogle Scholar
  23. 23.
    Rajneesh CP, Manimaran A, Sasikala KR, Adaikappan P (2008) Lipid peroxidation and antioxidant status in patients with breast cancer. Singap Med J 49(8):640–643Google Scholar
  24. 24.
    Diploc AT, Rice-Evans CA, Burdon RH (1994) Is there a significant role for lipid peroxidation in the causation of malignancy and for antioxidants in cancer prevention? Cancer Res 54:1952s–1956sGoogle Scholar
  25. 25.
    Beevi SSS, Rasheed AMH, Geetha A (2004) Evaluation of oxidative stress and nitric oxide levels in patients with oral cavity cancer. Jpn J Clin Oncol 34(7):379–385PubMedCrossRefGoogle Scholar
  26. 26.
    Sakuma S, Sumi H, Kohda T, Arakawa Y, Fujimoto Y (2009) Effects of lipid peroxidation-derived products on the growth of human colorectal cancer cell line HT-29. J Clin Biochem Nutr 45:171–177PubMedCrossRefGoogle Scholar
  27. 27.
    Ahmad R, Tripathi AK, Tripathi P, Singh R, Singh S, Singh RK (2010) Studies on lipid peroxidation and non-enzymatic antioxidant status as indices of oxidative stress in patients with chronic myeloid leukemia. Singap Med J 51(2):110–115Google Scholar
  28. 28.
    Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine, 4th edn. Oxford University, New YorkGoogle Scholar
  29. 29.
    Ravuri C, Svineng G, Pankiv S, Huseby NE (2011) Endogenous production of reactive oxygen species by the NADPH oxidase complexes is a determinant of gamma-glutamyl transferase expression. Free Rad Res 45(5):600–610CrossRefGoogle Scholar
  30. 30.
    Franco R, Cidlowski JA (2009) Apoptosis and glutathione: beyond an antioxidant. Cell Death Diff 16:1303–1314CrossRefGoogle Scholar
  31. 31.
    Clancy T, Pedicini M, Castiglione F, Santoni D, Nygaard V, Lavelle TJ, Benson M, Hovig E (2011) Immunological network signatures of cancer progression and survival. BMC Med Genomics 4(1):28PubMedCrossRefGoogle Scholar
  32. 32.
    Gomes AQ, Correia DV, Silva-Santos B (2007) Non-classical major histocompatibility complex proteins as determinants of tumor surveillance. EMBO rep 8:1024–1030PubMedCrossRefGoogle Scholar
  33. 33.
    Stewart TJ, Smyth MJ (2011) Improving cancer immunotherapy by targeting tumor-induced immune suppression. Cancer Metastasis Rev 30(1):125–140PubMedCrossRefGoogle Scholar
  34. 34.
    Negre-Salvayre A, Coatrieux C, Ingueneau C, Salvayre R (2008) Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors. Brit J Pharmacol 153:6–20CrossRefGoogle Scholar
  35. 35.
    Badid N, Ahmed FZ, Merzouk H, Belbraouet S, Mokhtari N, Merzouk SA, Benhabib R, Hamzaoui D, Narce M (2010) Oxidant/antioxidant status, lipids and hormonal profile in overweight women with breast cancer. Pathol Oncol Res 16(2):159–167PubMedCrossRefGoogle Scholar
  36. 36.
    Mannello F, Tonti GA, Medda V (2009) Protein oxidation in breast microenvironment: nipple aspirate fluid collected from breast cancer women contains increased protein carbonyl concentration. Cell Oncol 31(5):383–392PubMedGoogle Scholar
  37. 37.
    Bierie B, Moses HL (2009) Gain or loss of TGF-β signalling in mammary carcinoma cells can promote metastasis. Cell Cycle 8(20):319–3327CrossRefGoogle Scholar
  38. 38.
    DeMichelle A, Gray R, Horn M, Chen J, Aplenc R, Vaughan WP, Tallman MS (2009) Host genetic variants in the interleuin-6 promoter predict poor outcome in patients with estrogen-receptor-positive, node-positive breast cancer. Cancer Res 69(10):4184–4191CrossRefGoogle Scholar
  39. 39.
    Pelekanou V, Kampa M, Kafousi M, Darivianaki K, Sanidas E, Tsiftisis DD, Stathopoulos EM, Tsapis A, Castanas E (2008) Expression of TNF-superfamily members BAFF and APRIL in breast cancer: immunohistochemical study I 52 invasive ductal carcinomas. BMC Cancer 8:76–85PubMedCrossRefGoogle Scholar
  40. 40.
    Halliwell B (2007) Oxidative stress and cancer: have we moved forward? Biochem J 401(1):1–11PubMedCrossRefGoogle Scholar
  41. 41.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovzki A, Mlecnick B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PR, Trajanoski Z, Fridman WH, Pages F (2006) Type, density and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964PubMedCrossRefGoogle Scholar
  42. 42.
    Leek RD, Landers R, Fox SB, Ng F, Harris AL, Lewis CE (1998) Association of tumor necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma. Br J Cancer 77(12):2246–2251PubMedCrossRefGoogle Scholar
  43. 43.
    Reed JR, Leon RP, Hall MK, Schwertfeger KL (2009) Interleukin 1-beta and fibroblast growth factor receptor 1 cooperate to induce cyclooxygenase-2 during early mammary tumorigenesis. Breast Cancer Res 11:R21PubMedCrossRefGoogle Scholar
  44. 44.
    Nakamura Y, Yasuoka H, Tsujimoto M, Yoshidome K, Nakahara M, Nakao K, Nakamura M, Kakudo K (2006) Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis. Clin Cancer Res 12(4):1201–1207PubMedCrossRefGoogle Scholar
  45. 45.
    Menconi E, Barzi A, Greco M, Caprino MC, De Vecchis L, Muggia F (1979) Immunological profile of breast cancer patients in early and advanced disease. Experientia 35(6):820–822PubMedCrossRefGoogle Scholar
  46. 46.
    Mandeville R, Lamoureux G, Legault-Poisson S, Poisson R (1982) Biological markers and breast cancer. A multiparametric study. II: depressed immune competence. Cancer 50:1280–1288PubMedCrossRefGoogle Scholar
  47. 47.
    Merendino RA, Gangemi S, Misefari A, Arena A, Capozza AB, Chillemi S, Purello D’Ambrosio F (1999) Interleukin-12 and interleuki-10 production by mononuclear phagocytic cells from breast cancer patients. Immunol Lett 68:355–358PubMedCrossRefGoogle Scholar
  48. 48.
    Caras I, Grigorescu A, Stavaru C, Radu DL, Mogos I, Szegli G, Salageanu A (2004) Evidence for immune defects in breast and lung cancer patients. Cancer Immunol Imunnother 53:1146–1152CrossRefGoogle Scholar
  49. 49.
    Gruber IV, El Yousfi S, Durr-Storzer S, Wallwiener D, Solomayer EF, Fehm T (2008) Down-regulation of CD28, TCR-zeta and up-regulation of FAS in peripheral cytotoxic T cells of primary breast cancer patients. Anticancer Res 28(2):779–784PubMedGoogle Scholar
  50. 50.
    Gutteridge JMC (1984) Ferrous-ion EDTA-stimulated phospholipid peroxidation. Biochem J 224:697–701PubMedGoogle Scholar
  51. 51.
    Bacon BR, Tavill AS, Brittenham TM, Park CH (1983) Hepatic lipid peroxidation in vivo in rats with chronic iron overload. J Clin Invest 71:429–439PubMedCrossRefGoogle Scholar
  52. 52.
    Joo NS, Kim SM, Jung YS, Kim KM (2009) Hair iron and other minerals’ level in breast cancer patients. Biol Trace Elem Res 129:28–35PubMedCrossRefGoogle Scholar
  53. 53.
    Jian J, Yang Q, Dai J, Eckard J, Axelrod D, Smith J, Huang X (2011) Effects of iron deficiency and iron overload on angiogenesis and oxidative stress—a potential dual role for iron in breast cancer. Free Rad Biol Med 50:841–847PubMedCrossRefGoogle Scholar
  54. 54.
    Moore AB, Shannon J, Chen C, Lampe JW, Ray RM, Lewis SK, Lin M, Stalsberg H, Thomas DB (2009) Dietary and stored iron as predictors of breast cancer risk: a nested case-control study in Shangai. Int J Cancer 125(5):1110–1117PubMedCrossRefGoogle Scholar
  55. 55.
    Wink DA, Vodovotz Y, Laval J, Laval F, Dewhirst MW, Mitchell JB (1998) The multifaceted roles of nitric oxide in cancer. Carcinogenesis 19(5):711–721PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • C. Panis
    • 1
  • V. J. Victorino
    • 1
  • A. C. S. A. Herrera
    • 1
  • L. F. Freitas
    • 1
  • T. De Rossi
    • 1
  • F. C. Campos
    • 1
  • A. N. Colado Simão
    • 2
  • D. S. Barbosa
    • 2
  • P. Pinge-Filho
    • 3
  • R. Cecchini
    • 1
  • A. L. Cecchini
    • 1
  1. 1.Laboratório de Patologia e Radicais Livres, Departamento de Patologia Geral—Centro de Ciências BiológicasUniversidade Estadual de LondrinaLondrinaBrazil
  2. 2.Hospital Universitario, Departamento de FarmaciaUniversidade Estadual de LondrinaLondrinaBrazil
  3. 3.Laboratório de Imunopatologia, Departamento de Patologia Geral—Centro de Ciências BiológicasUniversidade Estadual de LondrinaLondrinaBrazil

Personalised recommendations