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

Jan 1, 2010Integrative cancer therapies

Nighttime melatonin slows breast cancer growth and metabolism depending on body clock stage, with light at night disrupting this effect in rats and women

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Abstract

Melatonin production during the night is inhibited by exposure to light, leading to increased tumor growth in breast cancer models.

Melatonin inhibits the uptake of linoleic acid and its conversion to a mitogenic compound in breast cancer.
Exposure to bright light at night increases tumor growth rates and metabolic activity in human breast cancer xenografts.
Circadian rhythms in linoleic acid uptake and tumor proliferation are disrupted by dim light exposure at night.
The findings suggest a potential link between night shift work and increased cancer risk in women.

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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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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

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