Roles of Oxidative Stress in the Development and Progression of Breast Cancer

  • Nourazarian, Ali Reza (Research Center for Pharmaceutical Nanotechnology, Faculty of Medicine, Tabriz University of Medical Sciences) ;
  • Kangari, Parisa (Department of Biology, Higher Education Institute of Rab) ;
  • Salmaninejad, Arash (Department of Medical Genetic, Faculty of Medicine, Tehran University of Medical Sciences)
  • Published : 2014.06.30


Oxidative stress is caused by an imbalance in the redox status of the body. In such a state, increase of free radicals in the body can lead to tissue damage. One of the most important species of free radicals is reactive oxygen species (ROS) produced by various metabolic pathways, including aerobic metabolism in the mitochondrial respiratory chain. It plays a critical role in the initiation and progression of various types of cancers. ROS affects different signaling pathways, including growth factors and mitogenic pathways, and controls many cellular processes, including cell proliferation, and thus stimulates the uncontrolled growth of cells which encourages the development of tumors and begins the process of carcinogenesis. Increased oxidative stress caused by reactive species can reduce the body's antioxidant defense against angiogenesis and metastasis in cancer cells. These processes are main factors in the development of cancer. Bimolecular reactions cause free radicals in which create such compounds as malondialdehyde (MDA) and hydroxyguanosine. These substances can be used as indicators of cancer. In this review, free radicals as oxidizing agents, antioxidants as the immune system, and the role of oxidative stress in cancer, particularly breast cancer, have been investigated in the hope that better identification of the factors involved in the occurrence and spread of cancer will improve the identification of treatment goals.


  1. Akram S, Teong HF, Fliegel L, Pervaiz S, Clement MV (2006). Reactive oxygen species-mediated regulation of the $Na^+$-$H^+$ exchanger 1 gene expression connects intracellular redox status with cells' sensitivity to death triggers. Cell Death Differ, 13, 628-41.
  2. Aldini G, Yeum K-J, Niki E, Russell RM (2010). Biomarkers For Antioxidant Defense And Oxidative Damage: Principles And Practical Applications. John Wiley and Sons, p363.
  3. Ali Soliman N, Arafa Keshk W, Salah Shoheib Z, et al (2014). Inflammation, oxidative stress and L-fucose as indispensable participants in schistosomiasis-associated colonic dysplasia. Asian Pac J Cancer Prev, 15, 1125-31.
  4. Ananda SK, Tragoolpua K, Chantawannakul P, Tragoolpua Y (2013). Antioxidant and anti-cancer cell proliferation activity of propolis extracts from two extraction methods. Asian Pac J Cancer Prev, 14, 6991-5.
  5. Artacho-Cordon F, Rios-Arrabal S, Lara P, et al (2012). Matrix metalloproteinases: potential therapy to prevent the development of second malignancies after breast radiotherapy. Surgi Oncol, 21, 143-51.
  6. Badid N, Ahmed FZB, Merzouk H, et al (2010). Oxidant/ antioxidant status, lipids and hormonal profile in overweight women with breast cancer. Pathol Oncol Res, 16, 159-67.
  7. Badjatia N, Satyam A, Singh P, Seth A, Sharma A (2010). Altered antioxidant status and lipid peroxidation in indian patients with urothelial bladder carcinoma. Urol Oncol, 28, 360-7.
  8. Barrera G (2012). Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncology, 2012, 1-21.
  9. Behrend L, Henderson G, Zwacka R (2003). Reactive oxygen species in oncogenic transformation. Biochem Soc Trans, 31, 1441-4.
  10. Bogdanovic V, Tursijan S, Dordevic M, et al (2008). Activity of lactate dehydrogenase and superoxide dismutase in the circulation of patients with breast carcinoma. Arch Oncol, 16, 39-41.
  11. Brown NS, Jones A, Fujiyama C, Harris AL, Bicknell R (2000). Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors. Cancer Res, 60, 6298-302.
  12. Brown NS, Bicknell R (2001). Hypoxia and oxidative stress in breast cancer. oxidative stress: its effects on the growth, metastatic potential and response to therapy of breast cancer. Breast Cancer Res, 3, 323-7.
  13. Chandra J, Samali A, Orrenius S (2000). Triggering and modulation of apoptosis by oxidative stress. Free Radical Biol Med, 29, 323-33.
  14. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A (2009). Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis, 30, 1073-81.
  15. Dayem AA, Choi H-Y, Kim J-H, Cho S-G (2010). Role of oxidative stress in stem, cancer, and cancer stem cells. Cancers, 2, 859-84.
  16. Delwar ZM, Vita MF, Ak S, Cruz M, Yakisich JS (2011). In vitro inhibition of topoisomerase $II\alpha$ by reduced glutathione. Acta Biochim Pol, 58, 265-7.
  17. El-Hefny MA, Karimova ST, Afandiev AM (2009). Lipid peroxidation and antioxidant status in breast cancer patients before and after therapy. Med J Cairo Univ, 77, 37-42.
  18. Fiaschi T, Chiarugi P (2012). Oxidative stress, tumor microenvironment and metabolic reprogramming: a diabolic liaison. Int J Cell Biology, 2012, 1-8.
  19. Gao CM, Takezaki T, Wu J-Z, et al (2003). Polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase genes and the susceptibility to esophageal and stomach cancer with smoking. Asian Pac J Cancer Prev, 5, 133-8.
  20. Gonenc A, Erten D, Aslan S, et al (2006). Lipid peroxidation and antioxidant status in blood and tissue of malignant breast tumor and benign breast disease. Cell Biol Int, 30, 376-80.
  21. Gonenc A, Tokgoz D, Aslan S, Torun M (2005). Oxidative stress in relation to lipid profiles in different stages of breast cancer. Indian J Bioch Biophisics, 42, 190-94.
  22. Gupta RK, Patel AK, Kumari R, et al (2012). Interactions between oxidative stress, lipid profile and antioxidants in breast cancer: a case control study. Asian Pac J Cancer Prev, 13, 6295-8.
  23. Halliwell B (2007). Oxidative stress and cancer: have we moved forward? Biochem J, 401, 1-11.
  24. Hwang ES, Bowen PE (2007). DNA damage, a biomarker of carcinogenesis: its measurement and modulation by diet and environment. Crc Cr Rev Food Sci, 47, 27-50.
  25. Izquierdo A, Gispert R, Saladie F, Espinas J (2008). Analysis of cancer incidence, survival and mortality according to the main tumoral localizations, 1985-2019: breast cancer. Med Clinica, 131, 50-2.
  26. Kim MC, Cui FJ, Kim Y (2013). Hydrogen peroxide promotes epithelial to mesenchymal transition and stemness in human malignant mesothelioma cells. Asian Pac J Cancer Prev, 14, 3625-30.
  27. Kimbro KS, Simons JW (2006). Hipoxia-inducible factor-1 in human breast and prostate cancer. Endocr Relat Cancer, 13, 739-49.
  28. Klaunig JE, Kamendulis LM, Hocevar BA (2010). Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol, 38, 96-109.
  29. Kruk J, Duchnik E (2014). Oxidative stress and skin diseases: possible role of physical activity. Asian Pac J Cancer Prev, 15, 561-8.
  30. Kwak MK, Wakabayashi N, Kensler TW (2004). Chemoprevention throughthe Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers. Mutat Res, 555, 133-48.
  31. Lee JJ, Lee JH, Ko YG, Hong SI, Lee JS (2009). Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species. Oncogene, 29, 561-75.
  32. Lin CW, Yang LY, Shen SC, Chen YC (2007). IGF-I plus E2 induces proliferation via activation of ros-dependent ERKs and JNKs in human breast carcinoma cells. J Cell Physiol, 212, 666-74.
  33. Martindale JL, Holbrook NJ (2002). Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol, 192, 1-15.
  34. Martinez Sarrasague M, Barrado DA, Zubillaga M, et al (2006). Current concepts of glutathione metabolism using stable isotopes for assessing homeostasis. Acta Bioquimica Clinica Latino, 40, 45-54.
  35. Matsuzawa A, Ichijo H (2008). Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling. Biochim et Biophys Acta (BBA)-Gen Subjects, 1780, 1325-36.
  36. Meijerman I, Beijnen JH, Schellens JH (2008). Combined action and regulationof phase II enzymes and multidrug resistance proteins in multidrug resistance in cancer. Cancer Treat Rev, 34, 505-20.
  37. Nelson NJ (2006). Migrant studies aid the search for factors linked to breast cancer risk. J Natl Cancer I, 98, 436-8.
  38. Nguyen T, Nioi P, Pickett CB (2009). The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem, 284, 13291-5.
  39. Noda N, Wakasugi H (2001). Cancer and oxidative stress. Japan Med Assn J, 44, 535-9.
  40. Omar ME AS, Eman RY, Hafez FH (2011). The antioxidant status of the plasma in patients with breast cancer undergoing chemotherapy. Open J Mol Integr Physiol, 1, 29-35.
  41. Park B, Shin A, Jung-Choi A, et al (2014). Correlation of breast cancer incidence with the number of motor vehicles and consumption of gasoline in Korea. Asian Pac J Cancer Prev, 15, 2959-64.
  42. Poli G, Leonarduzzi G, Biasi F, Chiarpotto E (2004). Oxidative stress and cell signalling. Curr Med Chem, 11, 1163-82.
  43. Pande D, Negi R, Khanna S, Khanna R, Khanna HD (2011). Vascular endothelial growth factor levels in relation to oxidative damage and antioxidant status in patients with breast cancer. J Breast Cancer, 14, 181-4.
  44. Rahman MA, Senga T, Ito S, et al (2010). S-nitrosylation at cysteine 498 of c-Src tyrosine kinase regulates nitric oxidemediated cell invasion. J Biol Chem, 285, 3806-14.
  45. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS (1996). Reactive oxygen species produced by macrophagederived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest, 98, 2572.
  46. Raj L, Ide T, Gurkar AU, et al (2012). Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature, 481, 531-4.
  47. Ramos-Gomez M, Dolan PM, Itoh K, Yamamoto M, Kensler TW (2003). Interactive effects of nrf2 genotype and oltipraz onbenzo[a]pyrene-DNA adducts and tumor yield in mice. Carcinog, 24, 461-7.
  48. Rios-Arrabal S, Artacho-Cordon F, Leon J, et al (2013). Involvement of free radicals in breast cancer. Springer Plus, 2, 1-12.
  49. Roy D, Sarkar S, Felty Q (2006). Levels of IL-1 beta control stimulatory/inhibitory growth of cancer cells. Front Biosci, 11, 889-98.
  50. Rust W, Kingsley K, Petnicki T, et al (1999). Heat shock protein 27 plays two distinct roles in controlling human breast cancer cell migration on laminin-5. Mol Cell Biol Res Comm, 1, 196-202.
  51. Schramek D, Kotsinas A, Meixner A, et al (2011). The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression. Nat Genet, 43, 212-9.
  52. Siegel R, Naishadham D, Jemal A (2013). Cancer statistics 2013. CA: Cancer J Clin, 63, 11-30.
  53. Sipe HJ, Jordan SJ, Hanna PM, Mason RP (1994). The metabolism of $17\beta$-estradiol by lactoperoxidase: a possible source of oxidative stress in breast cancer. Carcinog, 15, 2637-43.
  54. Sosa V, Moline T, Somoza R, et al (2013). Oxidative stress and cancer: an overview. Age Res Rev, 12, 376-90.
  55. Sreenivasa Rao CS, Sarala Kumari D (2012). Changes in plasma lipid peroxidation and the antioxidant system in women with breast cancer. Int J Basic Appl Sci, 1, 429-38.
  56. Storz P (2005). Reactive oxygen species in tumor progression. Front Biosci, 10, 1881-96.
  57. Surh YJ, Kundu JK, Na HK (2008). Nrf2 as a master redox switch in turningon the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med, 74, 1526-39.
  58. Swaim MW, Pizzo SV (1988). Methionine sulfoxide and the oxidative regulation of plasma proteinase inhibitors. J leukocyte Biol, 43, 365-79.
  59. Thiery JP (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2, 442-54.
  60. Tandon VR, Sharma S, Mahajan A, Bardi GH (2005). Oxidative stress: a novel strategy in cancer treatment. JK Science, 7, 1-3.
  61. Takada Y, Mukhopadhyay A, Kundu GC, et al (2003). Hydrogen peroxide activates NF-kappa B through tyrosine phosphorylation of I kappa B alpha and serine phosphorylation of p65: evidence for the involvement of I kappa B alpha kinase and Syk protein-tyrosine kinase. J Biol Chem, 278, 24233-41.
  62. Thiery JP (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2, 442-54.
  63. Valko M, Leibfritz D, Moncol J, et al (2007) Free radicals and antioxidants in normal physiological functions and human disease. The Int J Biochem Cell Biol, 39, 44-84.
  64. Valko M, Rhodes C, Moncol J, Izakovic M, Mazur M (2006). Free radicals, metals and antioxidants in oxidative stressinduced cancer. Chem Biol Interact, 160, 1-40.
  65. Vera-Ramirez L, Sanchez-Rovira P, Ramirez-Tortosa MC, et al (2011). Free radicals in breast carcinogenesis, breast cancer progression and cancer stem cells. biological bases to develop oxidative-based therapies. Crit Rev in Oncol Hematol, 80, 347-68.
  66. Vieira F, Di Pietro P, Boaventura B, et al (2011). Factors associated with oxidative stress in women with breast cancer. Nutr Hosp, 26, 528-36.
  67. Visvader JE, Lindeman GJ (2008). Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer, 8, 755-68.
  68. Wang XJ, Sun Z, Villeneuve NF, et al (2008). Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis, 29, 1235-43.
  69. Wang Y, Shang Y(2013). Epigenetic control of epithelial-tomesenchymal transition and cancer metastasis. Exp Cell Res, 319, 160-9.
  70. Wagner EF, Nebreda AR (2009). Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer, 9, 537-49.
  71. Waris G, Ahsan H (2006). Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinogenesis, 5, 14.
  72. Wiemer EA (2011). Stressed tumor cell, chemosensitized cancer. Nature medicine, 17, 1552-4.
  73. Yadav L, Puri N, Rastogi V, et al (2014). Matrix metallo proteinases and cancer - roles in threat and therapy. Asian Pac J Cancer Prev, 15, 1085-91.
  74. Yoshikawa T, Naito Y (2002). What is oxidative stress? JMAJ, 45, 271-6.
  75. Zhang HJ, Zhao W, Venkataraman S, et al (2002). Activation of matrix metalloproteinase-2 by overexpression of manganese superoxide dismutase in human breast cancer MCF-7 cells involves reactive oxygen species. J Biol Chem, 277, 20919-26.

Cited by

  1. Overweight, Obesity, Oxidative Stress and the Risk of Breast Cancer vol.15, pp.22, 2014,
  2. Mitochondrial DNA Copy Number in Peripheral Blood and Melanoma Risk vol.10, pp.6, 2015,
  3. Intrinsic Motivation Factors Based on the Self-Determinant Theory for Regular Breast Cancer Screening vol.15, pp.23, 2015,
  4. Lifestyle Components and Primary Breast Cancer Prevention vol.15, pp.24, 2015,
  5. Metastatic Inhibitory and Radical Scavenging Efficacies of Saponins Extracted from the Brittle Star (Ophiocoma erinaceus) vol.16, pp.11, 2015,
  6. Molecular Links between Alcohol and Tobacco Induced DNA Damage, Gene Polymorphisms and Patho-physiological Consequences: A Systematic Review of Hepatic Carcinogenesis vol.16, pp.12, 2015,
  7. Association between GSTP1 Genotypes and Hormone Receptor Phenotype in Invasive Ductal Carcinomas of Breast vol.16, pp.5, 2015,
  8. 2-deoxy-D-Glucose Synergizes with Doxorubicin or L-Buthionine Sulfoximine to Reduce Adhesion and Migration of Breast Cancer Cells vol.16, pp.8, 2015,
  9. The Many Virtues of tRNA-derived Stress-induced RNAs (tiRNAs): Discovering Novel Mechanisms of Stress Response and Effect on Human Health vol.290, pp.50, 2015,
  10. Inflammation-induced oxidative stress in breast cancer patients vol.32, pp.12, 2015,
  11. Paraoxonase and arylesterase activities in patients with papillary thyroid cancer vol.75, pp.3, 2015,
  12. Oxidative stress in Alzheimer disease and mild cognitive impairment: evidence from human data provided by redox proteomics vol.89, pp.10, 2015,
  13. Influence of oxidative injury and monitoring of blood plasma by DSC on breast cancer patients vol.123, pp.3, 2016,
  14. MICAL1 controls cell invasive phenotype via regulating oxidative stress in breast cancer cells vol.16, pp.1, 2016,
  15. Plasma Circulating Cell-free Nuclear and Mitochondrial DNA as Potential Biomarkers in the Peripheral Blood of Breast Cancer Patients vol.16, pp.18, 2016,
  16. Effect of Root Extracts of Medicinal Herb Glycyrrhiza glabra on HSP90 Gene Expression and Apoptosis in the HT-29 Colon Cancer Cell Line vol.16, pp.18, 2016,
  17. Ganglioside as a Therapy Target in Various Types of Cancer vol.17, pp.4, 2016,
  18. Reserpine Inhibit the JB6 P+ Cell Transformation Through Epigenetic Reactivation of Nrf2-Mediated Anti-oxidative Stress Pathway vol.18, pp.3, 2016,
  19. B Factor as Prognostic Markers in Mammary Tumors vol.2016, pp.1466-1861, 2016,
  20. Polymorphisms in DNA repair and oxidative stress genes associated with pre-treatment cognitive function in breast cancer survivors: an exploratory study vol.5, pp.1, 2016,
  21. Raman microspectroscopy for probing the impact of a dietary antioxidant on human breast cancer cells vol.7, pp.6, 2016,
  22. . Leaves vol.14, pp.4, 2017,
  23. Lethal and sublethal effects of a methomyl-based insecticide in Hoplobatrachus rugulosus vol.30, pp.1, 2017,
  24. Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms vol.8, pp.1663-9812, 2017,
  25. Serum antioxidant capacity, biochemical profile and body composition of breast cancer survivors in a randomized Mediterranean dietary intervention study pp.1436-6215, 2017,
  26. Sufrimiento en el trabajo y cuestiones de salud: el papel fundamental de la inflamación y el estrés oxidativo pp.19-1, 2017,
  27. Anticancer effects of saponin and saponin–phospholipid complex of Panax notoginseng grown in Vietnam vol.6, pp.9, 2016,
  28. Manganese Superoxide Dismutase Acetylation and Dysregulation, Due to Loss of SIRT3 Activity, Promote a Luminal B-Like Breast Carcinogenic-Permissive Phenotype vol.25, pp.6, 2016,
  29. Leptin induces ROS via NOX5 in healthy and neoplastic mammary epithelial cells vol.38, pp.5, 2017,
  30. Redox status in the sentinel lymph node of women with breast cancer vol.122, pp.4, 2017,
  31. Nutrients and Oxidative Stress: Friend or Foe? vol.2018, pp.1942-0994, 2018,
  32. Long-term exposure to road traffic noise and incidence of breast cancer: a cohort study vol.20, pp.1, 2018,
  33. Dietary Inflammatory Index and Odds of Breast Cancer in a Case-Control Study from Iran pp.1532-7914, 2018,