Skip to main content

Advertisement

SpringerLink
Log in

Melatonin, an inhibitory agent in breast cancer

  • Review Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

The heterogeneous nature of breast cancer makes it one of the most challenging cancers to treat. Due to the stimulatory effect of estrogen in mammary cancer progression, anti-estrogenic agents like melatonin have found their way into breast cancer treatment. Further studies confirmed a reverse correlation between nocturnal melatonin levels and the development of mammary cancer. In this study we reviewed the molecular inhibitory effects of melatonin in breast cancer therapy.

Methods

To open access the articles, Google scholar and science direct were used as a motor search. We used from valid external and internal databases. To reach the search formula, we determined mean key words like breast cancer, melatonin, cell proliferation and death. To retrieval the related articles, we continuously search the articles from 1984 to 2015. The relevance and the quality of the 480 articles were screened; at least we selected 80 eligible articles about melatonin molecular mechanism in breast cancer.

Result

The results showed that melatonin not only inhibits breast cancer cell growth, but also is capable of inhibiting angiogenesis, cancer cell invasion, and telomerase activity. Interestingly this hormone is able to induce apoptosis through the suppression or induction of a wide range of signaling pathways. Moreover, it seems that the concomitant administration of melatonin with other conventional chemotherapy agents had beneficial effects for patients with breast cancer, by alleviating unfavorable effects of those agents and enhancing their efficacy.

Conclusion

The broad inhibitory effects of melatonin in breast cancer make it a promising agent and may add it to the list of potential drugs in treatment of this cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Movahedi M, et al. Survival rate of breast cancer based on geographical variation in Iran, a national study. Iran Red Crescent Med J. 2012;14(12):798.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Turkoz FP, et al. Association between common risk factors and molecular subtypes in breast cancer patients. Breast. 2013;22(3):344–50.

    Article  PubMed  Google Scholar 

  3. Luo J et al. Association of active and passive smoking with risk of breast cancer among postmenopausal women: a prospective cohort study. BMJ. 2011;342:d1016.

  4. Ramezanpour H, Setayeshi S, Akbari M. 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 Prev. 2012;4(4):154–62.

    Google Scholar 

  5. Lissoni P, 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;71(4):854–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sánchez-Barceló EJ, et al. Melatonin–estrogen interactions in breast cancer. J Pineal Res. 2005;38(4):217–22.

    Article  PubMed  Google Scholar 

  7. Ozer H, et al. 2000 Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol. 2000;18(20):3558–85.

    CAS  PubMed  Google Scholar 

  8. Cohen M, Lippman M, Chabner B. Role of pineal gland in aetiology and treatment of breast cancer. Lancet. 1978;312(8094):814–6.

    Article  Google Scholar 

  9. Bartsch C, et al. Nocturnal urinary 6-sulphatoxymelatonin excretion is decreased in primary breast cancer patients compared to age-matched controls and shows negative correlation with tumor-size. J Pineal Res. 1997;23(2):53–8.

    Article  CAS  PubMed  Google Scholar 

  10. Rondanelli M, et al. Update on the role of melatonin in the prevention of cancer tumorigenesis and in the management of cancer correlates, such as sleep-wake and mood disturbances: review and remarks. Aging Clin Exp Res. 2013;25(5):499–510.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Dauchy RT, et al. Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer. Cancer Res. 2014;74(15):4099–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jung B, Ahmad N. Melatonin in cancer management: progress and promise. Cancer Res. 2006;66(20):9789–93.

    Article  CAS  PubMed  Google Scholar 

  13. Grant SG, et al. Melatonin and breast cancer: cellular mechanisms, clinical studies and future perspectives. Expert Rev Mol Med. 2009;11:e5.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005;9(1):11–24.

    Article  PubMed  Google Scholar 

  15. Srinivasan V, et al. Therapeutic actions of melatonin in cancer: possible mechanisms. Integr Cancer Ther. 2008;7(3):189–203.

    Article  CAS  PubMed  Google Scholar 

  16. Tricoire H, et al. Origin of cerebrospinal fluid melatonin and possible function in the integration of photoperiod. Reprod (Cambridge, England) Suppl. 2002;61:311–21.

    Google Scholar 

  17. Bonnefont-Rousselot D, Collin F. Melatonin: action as antioxidant and potential applications in human disease and aging. Toxicology. 2010;278(1):55–67.

    Article  CAS  PubMed  Google Scholar 

  18. Fernández-Mar M, et al. Bioactive compounds in wine: resveratrol, hydroxytyrosol and melatonin: a review. Food Chem. 2012;130(4):797–813.

    Article  Google Scholar 

  19. Reiter RJ, Tan D-X, Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res. 2010;181:127–51.

    Article  CAS  PubMed  Google Scholar 

  20. Miller SC, et al. The role of melatonin in immuno-enhancement: potential application in cancer. Int J Exp Pathol. 2006;87(2):81–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Montilla P, et al. Melatonin versus vitamin E as protective treatment against oxidative stress after extra-hepatic bile duct ligation in rats. J Pineal Res. 2001;31(2):138–44.

    Article  CAS  PubMed  Google Scholar 

  22. Morgan PJ, et al. Melatonin receptors: localization, molecular pharmacology and physiological significance. Neurochem Int. 1994;24(2):101–46.

    Article  CAS  PubMed  Google Scholar 

  23. Mao L, 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;56(3):246–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ebisawa T, et al. Expression cloning of a high-affinity melatonin receptor from Xenopus dermal melanophores. Proc Natl Acad Sci. 1994;91(13):6133–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reppert SM, et al. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci. 1995;92(19):8734–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nosjean O, et al. Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem. 2000;275(40):31311–7.

    Article  CAS  PubMed  Google Scholar 

  27. Becker-André M, et al. Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily. J Biol Chem. 1994;269(46):28531–4.

    PubMed  Google Scholar 

  28. Benitez-King G, Anton-Tay F. Calmodulin mediates melatonin cytoskeletal effects. Experientia. 1993;49(8):635–41.

    Article  CAS  PubMed  Google Scholar 

  29. Cutando A, et al. Role of melatonin in cancer treatment. Anticancer Res. 2012;32(7):2747–53.

    CAS  PubMed  Google Scholar 

  30. Kiefer T, et al. Melatonin inhibits estrogen receptor transactivation and cAMP levels in breast cancer cells. Breast Cancer Res Treat. 2002;71(1):37–45.

    Article  CAS  PubMed  Google Scholar 

  31. Lai L, et al. The Gαi and Gαq proteins mediate the effects of melatonin on steroid/thyroid hormone receptor transcriptional activity and breast cancer cell proliferation. J Pineal Res. 2008;45(4):476–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Witt-Enderby PA, et al. Melatonin receptors and their regulation: biochemical and structural mechanisms. Life Sci. 2003;72(20):2183–98.

    Article  CAS  PubMed  Google Scholar 

  33. Beckerandre M, Andre E, DeLamarter J. Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences. Biochem Biophys Res Commun. 1993;194(3):1371–9.

    Article  CAS  Google Scholar 

  34. Dong C, et al. Melatonin inhibits mitogenic cross-talk between retinoic acid-related orphan receptor alpha (RORα) and ERα in MCF-7 human breast cancer cells. Steroids. 2010;75(12):944–51.

    Article  CAS  PubMed  Google Scholar 

  35. Lai L, et al. Alteration of the MT1 melatonin receptor gene and its expression in primary human breast tumors and breast cancer cell lines. Breast Cancer Res Treat. 2009;118(2):293–305.

    Article  CAS  PubMed  Google Scholar 

  36. Jablonska K, et al. Expression of melatonin receptor MT1 in cells of human invasive ductal breast carcinoma. J Pineal Res. 2013;54(3):334–45.

    Article  CAS  PubMed  Google Scholar 

  37. Rögelsperger O, et al. Coexpression of the melatonin receptor 1 and nestin in human breast cancer specimens. J Pineal Res. 2009;46(4):422–32.

    Article  PubMed  Google Scholar 

  38. Oprea-Ilies G, et al. Expression of melatonin receptors in triple negative breast cancer (TNBC) in African American and Caucasian women: relation to survival. Breast Cancer Res Treat. 2013;137(3):677–87.

    Article  CAS  PubMed  Google Scholar 

  39. Mao L, et al. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cos S, et al. Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Res. 1998;58(19):4383–90.

    CAS  PubMed  Google Scholar 

  41. Cos S, Sánchez-Barceló EJ. Melatonin and mammary pathological growth. Front Neuroendocrinol. 2000;21(2):133–70.

    Article  CAS  PubMed  Google Scholar 

  42. Barceló EJS, Cos S. Melatonin, experimental basis for a possible application in breast cancer prevention and treatment. Histol Histopathol. 2000;15(2):637–47.

    Google Scholar 

  43. Sánchez-Barceló E et al. Melatonin: an endogenous antiestrogen with oncostatic properties. Melatonin From Molecules to Therapy. 2007;261–72.

  44. Hill SM, et al. The growth inhibitory action of melatonin on human breast cancer cells is linked to the estrogen response system. Cancer Lett. 1992;64(3):249–56.

    Article  CAS  PubMed  Google Scholar 

  45. Pandi-Perumal SR, et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol. 2008;85(3):335–53.

    Article  CAS  PubMed  Google Scholar 

  46. García Pedrero JM, et al. Calmodulin is a selective modulator of estrogen receptors. Mol Endocrinol. 2002;16(5):947–60.

    Article  PubMed  Google Scholar 

  47. Dai J, et al. Modulation of intracellular calcium and calmodulin by melatonin in MCF-7 human breast cancer cells. J Pineal Res. 2002;32(2):112–9.

    Article  CAS  PubMed  Google Scholar 

  48. del Río B, et al. Melatonin, an endogenous-specific inhibitor of estrogen receptor α via calmodulin. J Biol Chem. 2004;279(37):38294–302.

    Article  PubMed  Google Scholar 

  49. Conley A, Hinshelwood M. Mammalian aromatases. Reproduction. 2001;121(5):685–95.

    Article  CAS  PubMed  Google Scholar 

  50. Cos S, et al. Melatonin inhibits the growth of DMBA-induced mammary tumors by decreasing the local biosynthesis of estrogens through the modulation of aromatase activity. Int J Cancer. 2006;118(2):274–8.

    Article  CAS  PubMed  Google Scholar 

  51. Knower KC, et al. Melatonin suppresses aromatase expression and activity in breast cancer associated fibroblasts. Breast Cancer Res Treat. 2012;132(2):765–71.

    Article  CAS  PubMed  Google Scholar 

  52. Martínez-Campa C, et al. Melatonin enhances the inhibitory effect of aminoglutethimide on aromatase activity in MCF-7 human breast cancer cells. Breast Cancer Res Treat. 2005;94(3):249–54.

    Article  PubMed  Google Scholar 

  53. Martínez-Campa C, et al. Melatonin inhibits aromatase promoter expression by regulating cyclooxygenases expression and activity in breast cancer cells. Br J Cancer. 2009;101(9):1613–9.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Cos S, et al. Melatonin modulates aromatase activity in MCF-7 human breast cancer cells. J Pineal Res. 2005;38(2):136–42.

    Article  CAS  PubMed  Google Scholar 

  55. Wang J, et al. Simultaneous modulation of COX-2, p300, Akt, and Apaf-1 signaling by melatonin to inhibit proliferation and induce apoptosis in breast cancer cells. J Pineal Res. 2012;53(1):77–90.

    Article  CAS  PubMed  Google Scholar 

  56. Blask DE, et al. Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res. 2005;65(23):11174–84.

    Article  CAS  PubMed  Google Scholar 

  57. Collins A, et al. Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice. Cancer Lett. 2003;189(1):49–57.

    Article  CAS  PubMed  Google Scholar 

  58. Squecco R, et al. Melatonin affects voltage-dependent calcium and potassium currents in MCF-7 cell line cultured either in growth or differentiation medium. Eur J Pharmacol. 2015;758:40–52.

    Article  CAS  PubMed  Google Scholar 

  59. Jung JH et al. Melatonin suppresses the expression of 45S preribosomal RNA and upstream binding factor and enhances the antitumor activity of puromycin in MDA-MB-231 breast cancer cells. Evidence-Based Complementary and Alternative Medicine. 2013;2013:879746.

  60. Blask DE et al. Light exposure at night disrupts host/cancer circadian regulatory dynamics: impact on the Warburg effect, lipid signaling and tumor growth prevention. 2014;9(8):e102776.

  61. Hill SM, et al. Melatonin and associated signaling pathways that control normal breast epithelium and breast cancer. J Mammary Gland Biol Neoplasia. 2011;16(3):235–45.

    Article  PubMed  Google Scholar 

  62. Proietti S, et al. Molecular mechanisms of melatonin’s inhibitory actions on breast cancers. Cell Mol Life Sci. 2013;70(12):2139–57.

    Article  CAS  PubMed  Google Scholar 

  63. Proietti S, et al. Melatonin down-regulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells. J Pineal Res. 2014;57(1):120–9.

    Article  CAS  PubMed  Google Scholar 

  64. El-Aziz MAA, et al. The biochemical and morphological alterations following administration of melatonin, retinoic acid and Nigella sativa in mammary carcinoma: an animal model. Int J Exp Pathol. 2005;86(6):383–96.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Vriend J, Reiter RJ. Melatonin as a proteasome inhibitor. Is there any clinical evidence? Life Sci. 2014;115(1):8–14.

    Article  CAS  PubMed  Google Scholar 

  66. Proietti S, et al. Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells. J Pineal Res. 2011;50(2):150–8.

    CAS  PubMed  Google Scholar 

  67. Santoro R, et al. Melatonin triggers p53Ser phosphorylation and prevents DNA damage accumulation. Oncogene. 2012;31(24):2931–42.

    Article  CAS  PubMed  Google Scholar 

  68. Jardim-Perassi BV, et al. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PLoS ONE. 2014;9(1):e85311.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Alvarez-García V, et al. Antiangiogenic effects of melatonin in endothelial cell cultures. Microvasc Res. 2013;87:25–33.

    Article  PubMed  Google Scholar 

  70. Romon R, et al. Research Nerve growth factor promotes breast cancer angiogenesis by activating multiple pathways. Breast Cancer. 2010;9:11.

    Google Scholar 

  71. Blask D. The pineal: an oncostatic gland, in the pineal gland. New York: Raven Press; 1984. p. 253–84.

    Google Scholar 

  72. Anisimov VN, et al. The effect of melatonin treatment regimen on mammary adenocarcinoma development in HER-2/neu transgenic mice. Int J Cancer. 2003;103(3):300–5.

    Article  CAS  PubMed  Google Scholar 

  73. Mao L, et al. Circadian gating of epithelial-to-mesenchymal transition in breast cancer cells via melatonin-regulation of GSK3β. Mol Endocrinol. 2012;26(11):1808–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Leon-Blanco MM, et al. Melatonin inhibits telomerase activity in the MCF-7 tumor cell line both in vivo and in vitro. J Pineal Res. 2003;35(3):204–11.

    Article  CAS  PubMed  Google Scholar 

  75. Martínez-Campa CM, et al. Melatonin down-regulates hTERT expression induced by either natural estrogens (17β-estradiol) or metalloestrogens (cadmium) in MCF-7 human breast cancer cells. Cancer Lett. 2008;268(2):272–7.

    Article  PubMed  Google Scholar 

  76. Arif I, et al. Increasing doxorubicin activity against breast cancer cells using PPARγ-ligands and by exploiting circadian rhythms. Br J Pharmacol. 2013;169(5):1178–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ma C, et al. Protective and sensitive effects of melatonin combined with adriamycin on ER + (estrogen receptor) breast cancer. Eur J Gynaecol Oncol. 2014;36(2):197–202.

    Google Scholar 

  78. Mills E, et al. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res. 2005;39(4):360–6.

    Article  CAS  PubMed  Google Scholar 

  79. Alonso-González C, et al. Melatonin sensitizes human breast cancer cells to ionizing radiation by downregulating proteins involved in double-strand DNA break repair. J Pineal Res. 2015;58(2):189–97.

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by cancer research center, shahidbeheshti university of medical sciences.

Author information

Authors and Affiliations

  1. Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Elaheh Nooshinfar & Mohammad Esmaeil Akbari

  2. Department of Biology and Physiology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Elaheh Nooshinfar

  3. Department of Hematology and Blood banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Ava Safaroghli-Azar & Davood Bashash

Authors
  1. Elaheh Nooshinfar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ava Safaroghli-Azar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Davood Bashash
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad Esmaeil Akbari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elaheh Nooshinfar.

Ethics declarations

Conflict of interest

There is no conflict of interest.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nooshinfar, E., Safaroghli-Azar, A., Bashash, D. et al. Melatonin, an inhibitory agent in breast cancer. Breast Cancer 24, 42–51 (2017). https://doi.org/10.1007/s12282-016-0690-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-016-0690-7

Keywords

Search

Navigation