Cancer Causes & Control

, Volume 17, Issue 4, pp 515–523 | Cite as

Light During Darkness and Cancer: Relationships in Circadian Photoreception and Tumor Biology

  • Samar A. Jasser
  • David E. Blask
  • George C. Brainard
Special Section on Cancer and Rhythm Original Paper


The relationship between circadian phototransduction and circadian-regulated processes is poorly understood. Melatonin, commonly a circadian phase marker, may play a direct role in a myriad of physiologic processes. The circadian rhythm for pineal melatonin secretion is regulated by the hypothalamic suprachiasmatic nucleus (SCN). Its neural source of light input is a unique subset of intrinsically photosensitive retinal ganglion cells expressing melanopsin, the primary circadian photopigment in rodents and primates. Action spectra of melatonin suppression by light have shown that light in the 446–477 nm range, distinct from the visual system’s peak sensitivity, is optimal for stimulating the human circadian system. Breast cancer is the oncological disease entity whose relationship to circadian rhythm fluctuations has perhaps been most extensively studied. Empirical data has increasingly supported the hypothesis that higher risk of breast cancer in industrialized countries is partly due to increased exposure to light at night. Studies of tumor biology implicate melatonin as a potential mediator of this effect. Yet, causality between lifestyle factors and circadian tumor biology remains elusive and likely reflects significant variability with physiologic context. Continued rigorous empirical inquiry into the physiology and clinical implications of these habitual, integrated aspects of life is highly warranted at this time.


Melatonin Cancer Circadian rhythm Light Photoreception 



The authors appreciate the continuing support and assistance of John P. Hanifin in referencing and reviewing the manuscript. Primary support for this manuscript was provided by grants from NIEHS IR21ES11659, with valuable co-support from NCI 1RO1CA85408-01A2.


  1. 1.
    Hastings MH, Reddy AB, Maywood ES (2003) A clockwork web: circadian timing in brain and periphery, in health and disease. Nat Rev Neurosci 4:649–661CrossRefPubMedGoogle Scholar
  2. 2.
    Refinetti R (2000) Circadian Physiology. CRC Press, Boca Raton, Florida, 1–184Google Scholar
  3. 3.
    Stevens RG, Wilson BW, Anderson LE (eds) (1997) The Melatonin Hypothesis: Breast Cancer and Use of Electric Power. Columbus, Battelle Press, Ohio, pp 1–760Google Scholar
  4. 4.
    Brainard GC, Rollag MD, Hanifin JP (1997) Photic regulation of melatonin in humans: ocular and neural signal transduction. JBiol Rhythms 12:537–546PubMedGoogle Scholar
  5. 5.
    Brainard GC, Hanifin JP (2005) Photons, clocks and consciousness. J Biol Rhythms 20:314–325CrossRefPubMedGoogle Scholar
  6. 6.
    Reiter RJ, (1991) Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev 12:151–180PubMedGoogle Scholar
  7. 7.
    Brzezinski A, (1997) Melatonin in humans. N Engl J Med 336:186–195CrossRefPubMedGoogle Scholar
  8. 8.
    Lewy AJ, Sack RL, Miller LS, Hoban TM (1987) Antidepressant and circadian phase-shifting effects of light. Science 235:352–354PubMedGoogle Scholar
  9. 9.
    Lewy AJ, Bauer VK, Cutler NL, etal. (1998) Morning vs evening light treatment of patients with winter depression. Arch Gen Psychiatry 55:890–896PubMedGoogle Scholar
  10. 10.
    Terman JS, Terman M, Lo ES, Cooper TB (2001) Circadian time of morning light administration and therapeutic response in winter depression. Arch Gen Psychiatry 58:69–75PubMedGoogle Scholar
  11. 11.
    Lam RW (ed.) (1998) Seasonal Affective Disorder and Beyond: Light Treatment for SAD and Non-SAD Disorders. American Psychiatric Press, Washington, D.C., pp 1–327Google Scholar
  12. 12.
    Terman M, Terman JS, Ross DC (1998) A controlled trial of timed bright light and negative air ionization for treatment of winter depression. Arch Gen Psychiatry 55:875–882PubMedGoogle Scholar
  13. 13.
    Eastman CI, Young MA, Fogg LF, Liu L, Meaden PM (1998) Bright light treatment of winter depression: a placebo-controlled trial. Arch Gen Psychiatry 55:883–889PubMedGoogle Scholar
  14. 14.
    Tamarkin L, Danforth D, Lichter A, etal. (1982) Decreased nocturnal plasma melatonin peak in patients with estrogen receptor positive breast cancer. Science 216:1003–1005PubMedGoogle Scholar
  15. 15.
    Bartsch C, Bartsch H, Fuchs U, Lippert TH, Bellman O, Gupta D (1989) Stage-dependent depression of melatonin in patients with primary breast cancer. Cancer 64:426–433PubMedGoogle Scholar
  16. 16.
    Bartsch C, Bartsch H, Schmidt A, Ilg S, Bichler KH, Fluchter SH (1992) Melatonin and 6-sulfatoxymelatonin circadian rhythms in serum and urine or primary prostrate cancer patients: evidence for reduced pineal activity and relevance of urinary determinations. Clin Chim Acta 209:153–167CrossRefPubMedGoogle Scholar
  17. 17.
    Blask DE (1984) The pineal: an oncostatic gland? In: Reiter RJ (ed.) The Pineal Gland. Raven Press, New York, 253–284Google Scholar
  18. 18.
    Blask DE, Sauer LA, Dauchy RT, Holowachuk EW, Ruhoff MS, Kopff HE (1999) Melatonin inhibition of cancer growth in vivo involves suppression of tumor fatty acid metabolism via melatonin receptor-mediated signal transduction events. Cancer Res 59:4693–4701PubMedGoogle Scholar
  19. 19.
    Reiter RJ (1994) Melatonin: multifaceted messenger to the masses. Lab Med 25:438–443Google Scholar
  20. 20.
    Cos S, Blask DE (1994) Melatonin modulates growth factor activity in MCF-7 human breast cancer cells. J Pineal Res 17:25–32PubMedGoogle Scholar
  21. 21.
    Blask DE, Sauer LA, Dauchy RT (2002) 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 2:113–132CrossRefPubMedGoogle Scholar
  22. 22.
    Panzer A, Viljoen M (1997) The validity of melatonin as an oncostatic agent. J Pineal Res 22:184–202PubMedGoogle Scholar
  23. 23.
    Stevens RG, Rea MS (2001) Light in the built environment: potential role of circadian disruption in endocrine disruption and breast cancer. Cancer Causes Control 12:279–287CrossRefPubMedGoogle Scholar
  24. 24.
    Stevens RG (2001) Circadian disruption and breast cancer. In: Bartsch C, Bartsch H, Blask DE, Cardinali DP, Hrushesky WJM, Mecke D (eds) The Pineal Gland and Cancer: Neuroendocrine Mechanisms in Malignancy. Springer-Verlag, Berlin, 511–517Google Scholar
  25. 25.
    Lissoni P, Barni S, Meregalli S, etal. (1995) 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 71:854–856PubMedGoogle Scholar
  26. 26.
    Lissoni P, Meregalli S, Nosetto L, etal. (1996) Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 53:43–46PubMedGoogle Scholar
  27. 27.
    Gonzalez R, Sanchez A, Ferguson JA, etal. (1991) Melatonin therapy of advanced human malignant melanoma. Melanoma Res 1:237–243PubMedGoogle Scholar
  28. 28.
    Hill SM, Spriggs LL, Simon MA, Muraoka H, Blask DE (1992) The growth inhibitory action of melatonin on human breast cancer cells is linked to the estrogen response system. Cancer Lett 64:249–256CrossRefPubMedGoogle Scholar
  29. 29.
    Crespo D, Fernandez-Viadero C, Verduga R, Ovejero V, Cos S (1994) Interaction between melatonin and estradiol on morphological and morphometric features of MCF-7 human breast cancer cells. J Pineal Res 16:215–222PubMedGoogle Scholar
  30. 30.
    Nathan PJ, Norman TR, Burrows GD (1999) Effect of menstrual cycle stage on the melatonin suppression by dim white light. Psychoneuroendocrinology 24:193–200PubMedGoogle Scholar
  31. 31.
    Filipski E, Delaunay F, King VM, etal. (2004) Effects of chronic jet lag on tumor progression in mice. Cancer Res 64:7879–7885CrossRefPubMedGoogle Scholar
  32. 32.
    Lewy AJ, Sack RA, Singer CL (1984) Assessment and treatment of chronobiologic disorders using plasma melatonin levels and bright light exposure: the clock-gate model and the phase response curve. Psychopharmacol Bull 20:561–565PubMedGoogle Scholar
  33. 33.
    Klein DC, Moore RY, Reppert SM (eds) (1991) Suprachiasmatic Nucleus: The Mind’s Clock. Oxford University Press, Oxford, pp 5–456Google Scholar
  34. 34.
    Berson DM, Dunn FA, Takao M (2002) Phototransduction by retinal ganglion cells that set the circadian clock. Science 295:1070–1073CrossRefPubMedGoogle Scholar
  35. 35.
    Berson DM (2003) Strange vision: ganglion cells as circadian photoreceptors. Trends Neurosci 26:314–320CrossRefPubMedGoogle Scholar
  36. 36.
    Provencio I, Rollag MD, Castrucci AM (2002) Photoreceptive net in the mammalian retina. Nature 415:493CrossRefPubMedGoogle Scholar
  37. 37.
    Gooley JJ, Lu J, Fischer D, Saper CB (2003) A broad role for melanopsin in nonvisual photoreception. J Neurosci 23:7093–7106PubMedGoogle Scholar
  38. 38.
    Provencio I, Rodriguez IR, Jiang G, Hayes WP, Moreira EF, Rollag MD (2000) A novel human opsin in the inner retina. JNeurosci 20:600–605PubMedGoogle Scholar
  39. 39.
    Hannibal J, Hindersson P, Ostergaard J, etal. (2004) Melanopsin is expressed in PACAP-containing retinal ganglion cells of the human retinohypothalamic tract. Invest Ophthalmol Vis Sci 45:4202–4209CrossRefPubMedGoogle Scholar
  40. 40.
    Kumbalasiri T, Provencio I (2005) Melanopsin and other novel mammalian opsins. Exp Eye Res 81:368–375CrossRefPubMedGoogle Scholar
  41. 41.
    Partch CL, Sancar A (2005) Cryptochromes and circadian photoreception in animals. Methods Enzymol 393:726–745PubMedGoogle Scholar
  42. 42.
    Van Gelder RN (2005) Nonvisual ocular photoreception in the mammal. Methods Enzymol 393:746–755PubMedGoogle Scholar
  43. 43.
    Melyan Z, Tarttelin EE, Bellingham J, Lucas RJ, Hankins MW (2005) Addition of human melanopsin renders mammalian cells photoresponsive. Nature 433:741–745CrossRefPubMedGoogle Scholar
  44. 44.
    Qiu X, Kumbalasiri T, Carlson SM, etal. (2005) Induction of photosensitivity by heterologous expression of melanopsin. Nature 433:745–749CrossRefPubMedGoogle Scholar
  45. 45.
    Panda S, Nayak SK, Campo B, Walker JR, Hogenesch JB, Jegla T (2005) Illumination of melanopsins signaling pathway. Science 307:600–604CrossRefPubMedGoogle Scholar
  46. 46.
    Dacey DM, Liao H-W, Peterson BB, etal. (2005) Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN. Nature 433:749–754CrossRefPubMedGoogle Scholar
  47. 47.
    Pevet P, Heth G, Hiam A, Nevo E (1984) Photoperiod perception in the blind mole rat (Spalax ehrenbergi, Nehring): involvement of the Harderian gland, atrophied eyes, and melatonin. J Exp Zool 232:41–50CrossRefPubMedGoogle Scholar
  48. 48.
    Webb SM, Champney TH, Lewinski AK, Reiter RJ (1985) Photoreceptor damage and eye pigmentation: influence on the sensitivity of rat pineal N-acetyltransferase activity and melatonin levels to light at night. Neuroendocrinology 40:205–209PubMedGoogle Scholar
  49. 49.
    Foster RG, Provencio I, Hudson D, Fiske S, DeGrip W, Menaker M (1991) Circadian photoreception in the retinally degenerate mouse (rd/rd). J Comp Physiol [A] 169:39–50Google Scholar
  50. 50.
    Arendt J (1998) Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology. Rev Reprod 3:13–22PubMedGoogle Scholar
  51. 51.
    Brainard GC, Hanifin JP, Greeson JM, etal. (2001) Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci 21:6405–6412PubMedGoogle Scholar
  52. 52.
    Thapan K, Arendt J, Skene DJ (2001) An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans. J Physiol 535:261–267CrossRefPubMedGoogle Scholar
  53. 53.
    Brainard GC, Hanifin JP, Rollag MD, etal. (2001) Human melatonin regulation is not mediated by the three cone photopic visual system. J Clin Endocrinol Metab 86:433–436CrossRefPubMedGoogle Scholar
  54. 54.
    Lockley SW, Brainard GC, Czeisler CA (2003) High sensitivity of the human circadian melatonin rhythm to resetting by short wavelength light. J Clin Endocrinol Metab 88: 4502–4505CrossRefPubMedGoogle Scholar
  55. 55.
    Yoshimura T, Ebihara S (1996) Spectral sensitivity of photoreceptors mediating phase-shifts of circadian rhythms in retinally degenerate CBA/J (rd/rd) and normal CBA/N (+/+) mice. J Comp Physiol [A] 178:797–802Google Scholar
  56. 56.
    Ruby N, Brennan T, Xie X, etal. (2002) Role of melanopsin in circadian responses to light. Science 298:2211–2213CrossRefPubMedGoogle Scholar
  57. 57.
    Panda S, Sato TK, Castrucci AM, etal. (2002) Melanopsin (Opn4) requirement for normal light-induced circadian phase-shifting. Science 298:2213–2216CrossRefPubMedGoogle Scholar
  58. 58.
    Hankins MW, Lucas RJ (2002) The primary visual pathway in humans is regulated according to long-term light exposure through the action of a nonclassical photopigment. Curr Biol 12:191–198CrossRefPubMedGoogle Scholar
  59. 59.
    Morin LP, Blanchard JH, Provencio I (2003) Retinal ganglion cell projections to the hamster suprachiasmatic nucleus, intergeniculate leaflet, and visual midbrain: bifurcation and melanopsin immunoreactivity. J Comp Neurol 465:401–416CrossRefPubMedGoogle Scholar
  60. 60.
    Czeisler CA, Shanahan TL, Klerman EB, etal. (1995) Suppression of melatonin secretion in some blind patients by exposure to bright light. N Engl J Med 332:6–11CrossRefPubMedGoogle Scholar
  61. 61.
    Klerman EB, Shanahan TL, Brotman DJ, etal. (2002) Photic resetting of the human circadian pacemaker in the absence of conscious vision. J Biol Rhythms 17:548–555PubMedGoogle Scholar
  62. 62.
    Ruberg FL, Skene DJ, Hanifin JP, etal. (1996) Melatonin regulation in humans with color vision deficiencies. J Clin Endocrinol Metab 81:2980–2985CrossRefPubMedGoogle Scholar
  63. 63.
    Hahn RA (1991) Profound bilateral blindness and the incidence of breast cancer. Epidemiology 2:208–210PubMedGoogle Scholar
  64. 64.
    Feychting M, Osterlund B, Ahlbom A (1998) Reduced cancer incidence among the blind Epidemiology 9:490–494PubMedGoogle Scholar
  65. 65.
    Zacharias L, Wurtman RJ (1964) Blindness: its relation to the age of menarche. Science 144:1154–1155PubMedGoogle Scholar
  66. 66.
    Brainard GC, Lewy AJ, Menaker M, etal. (1988) Dose-response relationship between light irradiance and the suppression of melatonin in human volunteers. Brain Res 454:212–218CrossRefPubMedGoogle Scholar
  67. 67.
    Glickman G, Levin R, Brainard GC (2002) Ocular input for human melatonin regulation: relevance to breast cancer. Neuroendocrinol Lett 23:17–22PubMedGoogle Scholar
  68. 68.
    Zeitzer JM, Dijk D-J, Kronauer RE, Brown EN, Czeisler CA (2000) Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression. J Physiol 526: 695–702PubMedGoogle Scholar
  69. 69.
    Dauchy RT, Sauer LA, Blask DE, Vaughan GM (1997) Light contamination during the dark phase in “photoperiodically controlled” animal rooms: effect on tumor growth and metabolism in rats. Lab Anim Sci 47:511–518PubMedGoogle Scholar
  70. 70.
    Dauchy RT, Blask DE, Sauer LA, Brainard GC, Krause JA (1999) Dim light during darkness stimulates tumor progression by enhancing tumor fatty acid uptake and metabolism. Cancer Lett 144:131–136CrossRefPubMedGoogle Scholar
  71. 71.
    Aggelopoulos NC, Meissl H (2000) Responses of neurones of the rat suprachiasmatic nucleus to retinal illumination under photopic and scotopic conditions. J Physiol 523:211–222CrossRefPubMedGoogle Scholar
  72. 72.
    Smith KA, Schoen MW, Czeisler CA (2004) Adaptation of human pineal melatonin suppression by recent photic history. J Clin Endocrinol Metab 89:3610–3614PubMedGoogle Scholar
  73. 73.
    Hebert M, Martin SK, Lee C, Eastman CI (2002) The effects of prior light history on the suppression of melatonin by light in humans. J Pineal Res 33:198–203CrossRefPubMedGoogle Scholar
  74. 74.
    Brainard GC, Hanifin JP (2004) The effects of light on human health and behavior: relevance to architectural lighting. Vienna: CIE x027:2–16Google Scholar
  75. 75.
    Cajochen C, Munch M, Kobialka S, etal. (2005) High sensitivity of human melatonin, alertness, thermoregulation and heart rate to short wavelength light. J Clin Endocrinol Metab 90:1311–1316PubMedGoogle Scholar
  76. 76.
    Lipson ED (1994) Action spectroscopy: methodology. In: Horspool WM, Song P-S (eds) Organic Photochemistry and Photobiology. CRC Press, New York, 1257–1266Google Scholar
  77. 77.
    Matthes R, Sliney D, Didomenico S, Murray P, Phillips R, Wengraitis S (eds) (1999) Measurements of Optical Radiation Hazards. ICNIRP, Munchen, Germany, pp 1–762Google Scholar
  78. 78.
    Hrushesky WJM (2001) Melatonin cancer therapy. In: Bartsch C, Bartsch H, Blask DE, Cardinali DP, Hrushesky WJM, Mecke D (eds) The Pineal Gland and Cancer: Neuroendocrine Mechanisms in Malignancy. Springer-Verlag, Berlin, 476–508Google Scholar
  79. 79.
    Davis S, Mirick DK, Stevens RG (2001) Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 93:1557–1562PubMedGoogle Scholar
  80. 80.
    Schernhammer ES, Laden F, Speizer FE, etal. (2001) Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study. J Natl Cancer Inst 93:1563–1568PubMedGoogle Scholar
  81. 81.
    Parkin DM, Laara E, Muir CS (1988) Estimates of worldwide frequency of sixteen major cancers in 1980. Int J Cancer 41:184–197PubMedGoogle Scholar
  82. 82.
    Stevens RG (1987) Electric power use and breast cancer: a hypothesis. Am J Epidemiol 125:556–561PubMedGoogle Scholar
  83. 83.
    Stevens RG, Davis S (1996) The melatonin hypothesis: electric power and breast cancer. Environ Health Perspect 104:135–140PubMedGoogle Scholar
  84. 84.
    Blask DE, Dauchy RT, Sauer LA, Krause JA, Brainard GC (2003) Growth and fatty acid metabolism of human breast cancer (MCF-7) xenografts in nude rats: impact of constant light-induced nocturnal melatonin suppression. Breast Cancer Res Treat 79:313–320CrossRefPubMedGoogle Scholar
  85. 85.
    Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP (1980) Light suppresses melatonin secretion in humans. Science 210:1267–1269PubMedGoogle Scholar
  86. 86.
    Blask DE, Brainard GC, McGowan T, Kesselring J (2004) Relationship Between Light and the Development and Growth of Internal Solid Cancers: A Review of Current Research and the Potential Implications for Lighting Practice. EPRI, Palo Alto, CA, and McClung Foundation, Conyers, GA, 1011162Google Scholar
  87. 87.
    Blask DE, Dauchy RT, Sauer LA, Krause JA, Brainard GC (2002) Light during darkness, melatonin suppression and cancer progression. Neuroendocrinol Lett 23:52–56PubMedGoogle Scholar
  88. 88.
    Dauchy RT, Blask DE, Brainard GC, etal. (2003) Low-intensity light exposure during animal room dark phase and alterations in tumor growth rate and metablolism in rats: a dose-response relationship. Contemp TopLab Anim Sci 42:101Google Scholar
  89. 89.
    Nanda K, Bastian LA, Schulz K (2002) Hormone replacement therapy and the risk of death from breast cancer: a systematic review. Am J Obstet Gynecol 186:325–334CrossRefPubMedGoogle Scholar
  90. 90.
    Falkenberry SS, Legare RD (2002) Risk factors for breast cancer. Obstet Gynecol Clin North Am 29:159–172PubMedGoogle Scholar
  91. 91.
    MacMahon B, Cole P, Brown J (1973) Etiology of human breast cancer: a review. J Natl Cancer Inst 50:21–42PubMedGoogle Scholar
  92. 92.
    Kushi L, Giovannucci E (2002) Dietary fat and cancer. Amer J Med 113:63S–70SPubMedGoogle Scholar
  93. 93.
    Bianchini F, Kaaks R, Vainio H (2002) Overweight, obesity, and cancer risk. Lancet Oncol 3:565–574CrossRefPubMedGoogle Scholar
  94. 94.
    Giovannucci E (2002) Modifiable risk factors for colon cancer. Gastroenterol Clin North Am 31:925–943CrossRefPubMedGoogle Scholar
  95. 95.
    Ressel GW (2002) Amercan Cancer Society releases guidelines on nutrition and physical activity for cancer prevention. Am Fam Physician 66:1555, 1559–1560, 1562Google Scholar
  96. 96.
    White JD (2002) Cancer: current research in alternative therapies. Prim Care 29:379–392PubMedGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  • Samar A. Jasser
    • 1
  • David E. Blask
    • 2
  • George C. Brainard
    • 1
  1. 1.Department of Neurology, Light Research ProgramThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Laboratory of Chrono-Neuroendocrine OncologyBassett Research InstituteUSA

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