Could the amount of light, the time of day, or the season of the year affect cancer development and/or best possible time of treatment? The answer may lie in the study of circadian rhythms and chronobiology. The fact that some regulatory hormones are influenced by circadian rhythms may be critically important to cancer screening and chemotherapy administration.
The hormone melatonin, produced by the pineal gland in the brain and secreted at a rate that is suppressed by exposure to environmental lighting, is frequently cited as the key circadian hormone and one that is important in chronobiology.
Its role in cancer is quite different: Melatonin may act as an antioxidant that can scavenge free radicals and protect against DNA damage, and it regulates hormonal processes such as estrogen homeostasis. In patients undergoing chemotherapy, free radicals are thought to be a major source of toxicity, and in vitro, melatonin has been shown to reduce chemotherapy toxicity as well as promote apoptotic cell death.
Estrogen Receptors
How breast cancer cells with positive estrogen receptors respond to melatonin is one area of study. Steven Hill, Ph.D., professor in the Department of Structural and Cellular Biology at Tulane University School of Medicine in New Orleans, found that melatonin can inhibit the proliferation of estrogen receptorpositive breast cancer cells but has no effect on estrogen receptor-negative cells.
However, "there are different patterns of regulation of estrogen-modulated gene products which may involve multiple pathways, so use of melatonin as a treatment for ER-positive breast cancer is still something that needs more study," Hill said at a March workshop at the National Institutes of Health on circadian disruption as endocrine disruption in breast cancer, which was sponsored by the National Action Plan on Breast Cancer. Hill also said he thinks that melatonin may modulate apoptotic cell death by possibly affecting genes such as bcl-2, which has been shown to block apoptosis.
David Blask, Ph.D., M.D., senior research scientist at the Bassett Research Institute in Cooperstown, N.Y., has set up a model system to pursue this line of investigation. His system involves an in vivo liver tumor model that has shown an important relationship between nocturnal melatonin levels and tumor growth.
The effectiveness of giving melatonin during the day versus the night can often be critical. "Timing is important for melatonin administration and how exogenous administration can affect endogenous melatonin delivery and tumor responsiveness," said Blask. His studies have shown that melatonin suppression can accelerate tumor growth.
In 1998, the NCI Breast Cancer Progress Review Group concluded that their No. 1 research issue was trying to better understand normal mammary tissue development. Irma Russo, M.D., chief of the Molecular Endocrinology Section at the Fox Chase Cancer Center, Philadelphia, has been looking at normal mammary tissue development in rodents and humans and the impact that light has on this tissue.
"Varied lighting may play an important role in altering mammary gland development by effects on melatonin and estrogen," said Russo.
Photoreceptors
But just how the body is made aware of varied lighting is the subject of debate. Russell Foster, Ph.D., professor at the Imperial College School of Medicine, London, said that "it is not vision, but rather some other phototransduction system in the retina that causes suppression of melatonin in response to light." Fosters research shows that mice whose eyes are rodless and coneless still respond to light suppression of melatonin. He believes there is a new vitamin Abased opsin, a protein found in the retina, that may be responsible for this suppression.
While agreeing that a phototransduction system other than vision affects melatonin release, Aziz Sancar, M.D., Ph.D., professor at the University of North Carolina, Chapel Hill, disagreed with Foster and said that he believes a new class of photoreceptors called cryptochromes, which are vitamin B2 based, are responsible for response to light.
But what happens in women who are visually impaired? Richard Stevens, Ph.D., cancer epidemiologist at the University of Connecticut Health Center, Farmington, Conn., and chair of the NIH conference, and colleagues recently published a study in the British Journal of Cancer that found that breast cancer risk decreased by degree of visual impairment, from moderate low vision to totally blind. They concluded that this suggests a dose-response relationship between visible light and breast cancer risk.
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Epidemiological studies in Scandinavian countries have also suggested a relationship between degrees of visual impairment and cancer. A recent Swedish registry study noted that totally blind people have a lower cancer incidence compared with visually impaired people, and a Finnish cohort study showed a 15% higher cancer incidence for visually impaired versus totally blind people. However, neither of the studies is considered definitive, because causes other than higher melatonin exposure may be at work.
Increased cancer risk among flight personnel has previously been noted, including increased risk of breast cancer among flight attendants. Some have hypothesized that exposure to cosmic radiation and other physical or chemical agents may pose health risks for these personnel. "Time zone travel may disrupt circadian rhythms, altering melatonin levels, thus providing possible justification for the increase in breast cancer in flight attendants," said Stevens.
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