Circadian Stage-Dependent Inhibition of Human Breast Cancer Metabolism and Growth by the Nocturnal Melatonin Signal: Consequences of Its Disruption by Light at Night in Rats and Women

Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Integrative Cancer Therapies (Impact Factor: 2.36). 12/2009; 8(4):347-53. DOI: 10.1177/1534735409352320
Source: PubMed


The circadian production of melatonin by the pineal gland during the night provides an inhibitory signal to tissue-isolated steroid receptor SR+ and - MCF-7 human breast cancer xenografts in female nude rats. A pivotal mechanism for melatonin's anticancer effects in vivo involves a melatonin receptor-mediated inhibition of linoleic acid (LA) uptake and its metabolism to mitogenically active 13-hydroxyoctadecadienoic acid (13-HODE). Exposure of (SR-) xenograft-bearing rats to increasing intensities of polychromatic white light at night suppresses melatonin while increasing tumor growth rates, DNA content, [3H]thymidine incorporation into DNA, LA uptake, 13-HODE formation, cAMP levels and ERK1/2 activation a dose-dependent manner. Similar effects occur in SR- human breast cancer xenografts perfused in situ with melatonin-depleted blood from healthy female subjects after their exposure to a single bright intensity (2800 lux) of polychromatic light at night. Additionally, SR- human breast cancer xenografts exhibit robust circadian rhythms of LA uptake, 13-HODE formation and proliferative activity. Exposure of xenograft-bearing rats to dim light at night results in the complete elimination of these rhythms which culminates in unfettered, high rates of tumor metabolism and growth. The organization of tumor metabolism and growth within circadian time structure by the oncostatic melatonin signal helps create a balance between the cancer and its host that is disrupted by host exposure to light at night. This biological mechanism may partially explain the higher risk of breast and other cancers in women working rotating night shifts and possibly others who also experience prolonged exposure to light at night.

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    • "In humans, decreased melatonin levels are found in patients with Alzheimer's disease (Liu et al., 1999; Mishima et al., 1999), age-related macular degeneration (Rosen et al., 2009); or autism spectrum disorders (Melke et al., 2008; Nir et al., 1995; Tordjman et al., 2005). In addition, disrupted melatonin production in shift workers is considered a risk factor for increased breast cancer rates (Blask et al., 2009). It is therefore critical to define the key step of melatonin synthesis in vivo. "
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