Melatonin-Depleted Blood from Premenopausal Women Exposed to Light at Night Stimulates Growth of Human Breast Cancer Xenografts in Nude Rats

Abstract

The increased breast cancer risk in female night shift workers has been postulated to result from the suppression of pineal melatonin production by exposure to light at night. Exposure of rats bearing rat hepatomas or human breast cancer xenografts to increasing intensities of white fluorescent light during each 12-hour dark phase (0-345 MW/cm 2 ) resulted in a dose-dependent suppression of nocturnal melatonin blood levels and a stimulation of tumor growth and linoleic acid uptake/metabolism to the mitogenic molecule 13-hydroxyoctadecadienoic acid. Venous blood samples were collected from healthy, premenopausal female volunteers during either the daytime, nighttime, or nighttime following 90 minutes of ocular bright, white fluorescent light exposure at 580 MW/cm 2 (i.e., 2,800 lx). Compared with tumors perfused with daytimecollected melatonin-deficient blood, human breast cancer xenografts and rat hepatomas perfused in situ, with nocturnal, physiologically melatonin-rich blood collected during the night, exhibited markedly suppressed proliferative activity and linoleic acid uptake/metabolism. Tumors perfused with melatonin-deficient blood collected following ocular exposure to light at night exhibited the daytime pattern of high tumor proliferative activity. These results are the first to show that the tumor growth response to exposure to light during darkness is intensity dependent and that the human nocturnal, circadian melatonin signal not only inhibits human breast cancer growth but that this effect is extinguished by short-term ocular exposure to bright, white light at night. These mechanistic studies are the first to provide a rational biological explanation for the increased breast cancer risk in female night shift workers. (Cancer Res 2005; 65(23): 11174-84)

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…Melatonin may exert its suppressive effects on tumor linoleic acid metabolism via a MT 1 melatonin receptor-mediated reduction in cAMP formation. Blask et al [89] demonstrated that in human breast cancer xenografts, suppression of the circadian amplitude of nocturnal melatonin production causes a significant increase in linoleic acid uptake and its conversion to 13-HODE, stimulating tumor growth. Light at night suppresses the direct antiproliferative effects of endogenous melatonin on human cancer [90,91].…”

“…Light at night suppresses the direct antiproliferative effects of endogenous melatonin on human cancer [90,91]. Therefore, some antitumor effects of melatonin correlate with melatonin receptor (MT 1 / MT 2 )-dependent inhibition of linoleic acid uptake [89]. In addition, melatonin could suppress the Warburg effect by reducing 13-HODE formation and thus activation of AKT, which is a major stimulatory pathway for aerobic glycolysis [92].…”

Short-term effects of night shift work on breast cancer risk: a cohort study of payroll data

“…From animal studies it is known that melatonin reduces the growth of chemically induced mammary tumors (10,14). It has also been shown that melatonin at physiological levels suppresses the proliferation of human breast cancer xenografts (15)(16)(17). Furthermore, melatonin may reduce the invasiveness of human breast cancer, and the suppression of melatonin during the biological night may act as a promoter of oncogenesis (10,16).…”

Association of Breast Cancer with Sleep Pattern - A Pilot Case Control Study in a Regional Cancer Centre in South Asia

“…Cohen et al (1978) proposed that reduced production of the hormone melatonin might increase the risk of breast cancer and citing "environmental lighting" as a possible causal factor. Blask et al (2005) at the National Cancer Institute (NCI) and National Institute of Environmental Health Sciences conducted a study in 2005 that suggests that artificial light during the night can be a factor for breast cancer by disrupting melatonin levels.…”