Melatonin and its importance in Breast cancer prevention and treatment (A purposed review article)

Document Type : Review Article


1 Assistant professor, Department of Molecular Cellular Biology, Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Assistant professor, Department of Hematology, School of Paramedics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 M.Sc. of Midwifery, Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

4 M.Sc. of Microbiology, Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

5 M.Sc. of Biophysics, Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

6 M.Sc. of Psychology, Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

7 Professor, Department of cancer surgery, Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.


Introduction: Breast cancer is always one of the most important difficulties in women's health that causes serious physical، mental and economical harms for the patient and her family. Nowadays, molecular therapies have been considered by the researchers. Used drugs act through different molecular mechanisms and prevents from breast cancer developing; a lot of proteins play a role in these mechanisms including melatonin has a specific role. For this reason, recognizing melatonin functions and executive mechanisms, related genes and orientation with melatonin news and also its benefits in breast cancer will help us to design new and efficient molecular methods in treatment and management of breast cancer. This study was performed with the aim to review recognized mechanisms by melatonin in breast cancer treatment till now.
Methods: To open access the articles, we searched from valid internal and external databases. For research formula, at first, we determine main key words, then equivalent terms were identified, and using appropriate operators, the formula was developed. The results were screened and the relevant articles were selected. Finally, 55 articles about breast cancer molecular biology and Melatonin function mechanism were selected and based on them, the review was done. 
Results: The wide function domain of Melatonin in breast cancer includes induction of apoptosis، telomerase and inhibition of epidermal growth factor bridle in breast cancer, cell cycle inhibition, stimulation of immune system to destroy cancer cells, repair of damaged DNA, the regulation of daily and seasonal rhythm and also angiogenesis inhibition. The role of melatonin as an oncostatics and oncocytotoxic factor leads to believe melatonin application as a supplement factor in breast cancer treatment.
Conclusions: The safety of Melatonin along with its benefits introduces it as a suitable candidate to improve treatment methods for breast cancer patients.


  1. Movahedi M, Haghighat S, Khayamzadeh M, Moradi A, Ghanbari-Motlagh A, Mirzaei H, et al. Survival rate of breast cancer based on geographical variation in Iran, a national study. Iran Red Crescent Med J 2012 Dec;14(12):798-804.
  2. Available at: See comment in PubMed Commons‎.
  3. Ramezanpour HR, Setayeshi S, Akbari ME. A novel scheme for optimal control of a nonlinear delay differential equations model to determine effective and optimal administrating chemotherapy agents in breast cancer. Iran J Cancer Preven 2012;4(4):154-62..
  4. Akbari ME, Khayamzadeh M, Khoshnevis S, Nafisi N, Akbari A. Five and ten years survival in breast cancer patients mastectomies vs. breast conserving surgeries personal experience. Iran J Cancer Preven 2008 Apr;1(2):53-6.
  5. Akbari ME, Mozaffar M, Heidari A, Zirakzadeh H, Akbari A, Akbari M, et al. Recurrence and survival effect in breast conserving surgery: what are the predictive and/or prognostic factors? Iran J Cancer Preven 2011;4(2):49-54.
  6. Safaei A, Rezaei-Tavirani M, Sobhi S, Akbari ME. Breast cancer biomarker discovery: proteomics and genomics approaches. Iran J Cancer Preven 2013 Winter;6(Suppl):45-53.
  7. Khoshnevis N,  Shahid Sales S,  Alizadeh M, Mirsadraei M, Akbari ME. [Nutritional assessment of cancer patients by PG-SGA questionnaire in Cancer Research Center (CRC) of Shahid Beheshti University of Medical Sciences, Tehran, Iran, 2010] [Article in Persian]. 2012;36(3):132-8.
  8. Haghighat S, Akbari ME, Ghaffari S, Yavari P. Standardized breast cancer mortality rate compared to the general female population of Iran. Asian Pac J Cancer Prev 2012;13(11):5525-8.
  9. Nafissi N, Saghafinia M, Motamedi MH, Akbari ME. A survey of breast cancer knowledge and attitude in Iranian women. J Cancer Res Ther 2012 Jan-Mar;8(1):46-9.
  10. Mohammadzade J, Amirrassouli H, Akbari ME, Javanmard B, Kazerouni F, Namaki S, et al. Comparative study of serum levels of Granzyme H & Estrogen in patients suffering from breast cancer. J Paramed Sci 2013 Winter;4(Sppl):26-8.
  11. Safaee Keshtgar MR, Stin R. Breast canser. Tehran:Vajeh No;2010.
  12. Noori-Daloii MR, Shahriar Hesami S. [Telomerase and it's inhibition in cancer: a review article] [Article in Persian]. Tehran Univ Med J 2009 Dec;67(9):599-607.
  13. Weinberg RA. The biology of cancer. New York:Garland Science;2007.
  14. Mao L, Yuan L, Slakey LM, Jones FE, Burow ME, Hill SM. Inhibition of breast cancer cell invasion by melatonin is mediated through regulation of the p38 mitogen-activated protein kinase signaling pathway. Breast Cancer Res 2010;12(6):R107.
  15. Keshavarzi F, Javadi GR, Nafissi N, Akbari ME, Yassaee VR, Sharafi Farzad M, et al. [BRCA1 and BRCA2 genetic testing in breast and/or ovarian cancer families in Iran] [Article in Persian]. Cell J (Yakhteh) 2010;12(3);329-40.
  16. Keshavarzi F, Javadi GR, Nafissi N, Majidzadeh K, Yassaee VR, Bagherian H, et al. [Identification in BRCA1 and BRCA2 mutation in a number of Iranian patients with early onset breast cancer or family history of breast cancer risk] [Article in Persian]. Iran J Breast Dis 2009;2(2):14-26.
  17. Fasching PA, Heusinger K, Haeberle L, Niklos M, Hein A, Bayer CM, et al. Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment. BMC Cancer 2011;11(1):486.
  18. Mittal A, Pate MS, Wylie RC, Tollefsbol TO, Katiyar SK. EGCG down-regulates telomerase in human breast carcinoma MCF-7 cells, leading to suppression of cell viability and induction of apoptosis. Int J Oncol 2004 Mar;24(3):703-10.
  19. Reed JC. Apoptosis-based therapies. Nat Rev Drug Discov 2002 Feb;1(2):111-21.
  20. Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med 1997 Jun;3(6):614-20.
  21. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998 Aug 28;281(5381):1305-8.
  22. Leon‐Blanco MM, Guerrero JM, Reiter RJ, Calvo JR, Pozo D. Melatonin inhibits telomerase activity in the MCF‐7 tumor cell line both in vivo and in vitro. J Pineal Res 2003 Oct;35(3):204-11.
  23.  Hill SM, Spriggs LL, Simon MA, Muraoka H, Blask DE. The growth inhibitory action of melatonin on human breast cancer cells is linked to the estrogen response system. Cancer Lett 1992 Jul 10;64(3):249-56.
  24. Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta‐analysis. J Pineal Res 2005 Nov;39(4):360-6.
  25. Martín‐Renedo J, Mauriz JL, Jorquera F, Ruiz‐Andrés O, González P, González‐Gallego J. Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. J Pineal Res 2008 Nov;45(4):532-40.
  26. Eck-Enriquez K, Kiefer TL, Spriggs LL, Hill SM. Pathways through which a regimen of melatonin and retinoic acid induces apoptosis in MCF-7 human breast cancer cells. Breast Cancer Res Treat 2000 Jun;61(3):229-39.
  27. Mao L, Yuan L, Xiang S, Zeringue SB, Dauchy RT, Blask DE, et al. Molecular deficiency (ies) in MT1 melatonin signaling pathway underlies the melatonin‐unresponsive phenotype in MDA‐MB‐231 human breast cancer cells. J Pineal Res 2014 Apr;56(3):246-53.
  28. Leonardi GC, Rapisarda V, Marconi A, Scalisi A, Catalano F, Proietti L, et al. Correlation of the risk of breast cancer and disruption of the circadian rhythm (Review). Oncol Rep 2012 Aug;28(2):418-28.
  29. Bracci M, Copertaro A, Manzella N, Staffolani S, Strafella E, Nocchi L, et al. Influence of night-shift and napping at work on urinary melatonin, 17-ß-estradiol and clock gene expression in pre-menopausal nurses. J Biol Regul Homeost Agents 2012 Jan-Mar;27(1):267-74.
  30. Naziroglu M, Tokat S, Demirci S. Role of melatonin on electromagnetic radiation-induced oxidative stress and Ca2+ signaling molecular pathways in breast cancer. J Recept Signal Transduct Res 2012 Dec;32(6):290-7.
  31. Li W, Ray RM, Thomas DB, Yost M, Davis S, Breslow N, et al. Occupational exposure to magnetic fields and breast cancer among women textile workers in Shanghai, China. Am J Epidemiol 2013 Oct 1;178(7):1038-45.
  32. Liu R, Fu A, Hoffman AE, Zheng T, Zhu Y. Melatonin enhances DNA repair capacity possibly by affecting genes involved in DNA damage responsive pathways. BMC Cell Biol 2013 Jan 7;14:1. doi: 10. 11865/1471-2121-141-1.
  33. Nasrabadi NN, Ataee R, Abediankenari S, Shokrzadeh M, Najafi M, Hoseini SV, et al. Expression of MT2 receptor in patients with gastric adenocarcinoma and its relationship with clinicopathological features. J Gastrointest Cancer 2014 Mar;45(1):54-60..
  34. Wang XS, Tipper S, Appleby PN, Allen NE, Key TJ, Travis RC. First-morning urinary melatonin and breast cancer risk in the Guernsey Study. Am J Epidemiol 2014 Mar 1;179(5):584-93.
  35. Jardim-Perassi BV, Arbab AS, Ferreira LC, Borin TF, Varma NR, Iskander A, et al. Effect of Melatonin on Tumor Growth and Angiogenesis in Xenograft Model of Breast Cancer. PloS One 2014 Jan 9;9(1):e85311.
  36. Bracci M, Manzella N, Copertaro A, Staffolani S, Strafella E, Barbaresi M, et al. Rotating-shift nurses after a day off: peripheral clock gene expression, urinary melatonin, and serum 17-β-estradiol levels. Scand J Work Environ Health 2014 May 1;40(3):295-304.
  37. Kelleher FC, Rao A, Maguire A. Circadian molecular clocks and cancer. Cancer Lett 2014 Jan 1;342(1):9-18.
  38. Di Bella G, Mascia F, Ricchi A, Colori B. Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report. Neuro Endocrinol Lett 2013 Dec 27;34(7):660-8.
  39. Ghaderi R, Sehatbakhsh S, Bakhshaee M, Sharifzadeh GR. Urinary melatonin levels and skin malignancy. Iran J Med Sci 2014 Jan;39(1):64-7.
  40. Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, et al. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther 2012 Dec;11(4):293-303.
  41. Reiter RJ, Tan DX, Manchester LC, Pilar Terron M, Flores LJ, Koppisepi S. Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv Med Sci 2007;52:11-28.
  42. Jung B, Ahmad N. Melatonin in cancer management: progress and promise. Cancer Res 2006 Oct 15;66(20):9789-93.
  43. Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev 2005 Feb;9(1):11-24.
  44. Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem 2002 Feb;2(2):113-32.
  45. Martín V, Herrera F, Carrera-Gonzalez P, García-Santos G, Antolín I, Rodriguez-Blanco J, et al. Intracellular signaling pathways involved in the cell growth inhibition of glioma cells by melatonin. Cancer Res 2006 Jan 15;66(2):1081-8.
  46. Sanchez-Barcelo EJ, Cos S, Fermandez R, Mediavilla MD. Melatonin and mammary cancer: a short review. Endocr Relat Cancer 2003 Jun;10(2):153-9.
  47. Lissoni P, Barni S, Meregalli S, Fossati V, Cazzaniga M, Esposti D, et al. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer 1995 Apr;71(4):854-6.
  48. Jordan VC, MURPHY CS. Endocrine pharmacology of antiestrogens as antitumor agents. Endocr Rev 1990 Nov;11(4):578-610.
  49. Lissoni P, Barni S, Mandala M, Ardizzoia A, Paolorossi F, Vaghi M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer 1999 Nov;35(12):1688-92.
  50. Kaczor T. An overview of melatonin and breast cancer: exploring metatonin's has unique effects on breast cancer cells. Nat Med J 2010;2(2). Available at:
  52. Miller SC, Pandi-Perumal SR, Esquifino AI, Cardinali DP, Maestroni GJ. The role of melatonin in immuno‐enhancement: potential application in cancer. Int J Exp Pathol 2006 Apr;87(2):81-7.
  53. Omar SH, Saba N. Melatonin, receptors, mechanism, and uses. Syst Rev Pharmacy 2010;1(2:158.
  54. Cutando A, Lopez-Valverde A, Arias-Santiago S, DE Vicente J, DE Diego RG. Role of melatonin in cancer treatment. Anticancer Res 2012 Jul;32(7):2747-53.
  55. Sturgeon SR, Doherty A, Reeves KW, Bigelow C, Stanczyk FZ, Ockene JK, et al. Urinary levels of melatonin and risk of postmenopausal breast cancer: women's health initiative observational cohort. Cancer Epidemiol Biomarkers Prev 2014 Apr;23(4):629-37.
  56. Haus EL, Smolensky MH. Shift work and cancer risk: potential mechanistic roles of circadian disruption, light at night, and sleep deprivation. Sleep Med Rev 2013 Aug;17(4):273-84.