Mini-reviewCirculating melatonin and the risk of breast and endometrial cancer in women
Introduction
Melatonin (N-acetyl-5-methoxytryptamine), a hormone produced primarily by the pineal gland, appears to protect against cancer development. Melatonin biosynthesis depends on dietary intake of the essential amino acid tryptophan, which is converted to serotonin and subsequently metabolized to melatonin by the enzyme hydroxyindole-O-methyltransferase (HIOMT) [1]. Normal melatonin daytime serum levels range from 1.4 to 2.1 pg/ml [2]. Melatonin exerts its actions by binding to nuclear receptors that belong to the RZR/ROR family and membrane receptors MT1, MT2, and MT3, the mRNA expression of which fluctuates based on the circadian rhythm, the melatonin plasma concentration and the amount of light [3], [4], [5].
Several authors have proposed that nighttime shift workers have altered melatonin levels and are more likely to develop cancer, including breast and endometrial cancer in women [6], [7], [8]. In 2007, a total of 178,480 cases of female breast cancer were diagnosed in the U.S., making it the most frequently diagnosed cancer among women [9]. Known risk factors include age, family or personal history of breast cancer, high breast tissue density, atypical hyperplasia, a history of chest radiation, early menarche, nulliparity, recent use of oral contraceptives, age of birth of first child over 30, obesity after menopause, physical inactivity, and consumption of one or more alcoholic beverages a day [10]. Endometrial cancer was the most common gynecologic malignancy in the U.S. in 2007, with over 40,000 new cases and approximately 7000 deaths [11]. Risk factors for endometrial cancer include factors that increase unopposed estrogen exposure, including obesity, postmenopausal hormone use, nulliparity, older age at first birth, early menarche, and late menopause [12]. Smoking and oral contraceptive use decrease risk [13]. This review will explore the current epidemiologic evidence on nighttime workers and the association between melatonin and breast and endometrial cancer risk in women, as well as discuss possible mechanisms by which melatonin may act specifically to reduce breast and endometrial cancer risk among women.
Section snippets
Melatonin: possible oncostatic mechanisms
Experimental studies suggest that the antineoplastic action of melatonin arises through myriad possible routes, including antioxidant, antimitotic, and/or antiangiogenic activity, as well as its ability to modulate the immune system and alter fat metabolism. More generally, melatonin may have regulatory signaling functionality in that it appears to regulate initiation, promotion, and/or progression of cancer [14], [15]. Thus, the decrease in serum melatonin seen in night workers may enhance
Sleep duration, night shift work, and association with melatonin production
In humans, melatonin secretion is regulated by the hypothalamus, which receives environmental light signals from the retina via the retino-hypothalamic tract. Artificial light alters the natural release of melatonin, with highest levels of melatonin physiologically occurring during the dark night phase and relatively low levels throughout the day [38].
Early evidence from retrospective studies of melatonin and breast cancer risk
Several authors have proposed that the reduction in melatonin seen in night shift workers may be related to an increased risk of breast cancer [48]. The first report to evaluate an association between circulating melatonin levels and breast cancer risk in 10 women was conducted by Bartsch et al. in 1981. It found in a small sample of women with advanced breast cancer, when compared with healthy controls, that they had lower levels of urinary melatonin [66]. Subsequently, Tamarkin et al. found
Endometrial cancer
Prior evidence indicates that women with endometrial cancer have lower melatonin levels [83]. Whether or not an MT2 melatonin receptor subtype found in a human endometrial cancer cell line may mediate the cancer protective effect of melatonin is not clear [84]. In 2007, the first prospective cohort study of shift work and endometrial cancer was published, and demonstrated that the risk of endometrial cancer was significantly elevated among women with 20 or more years work on rotating night
Conclusion
Melatonin exhibits several oncostatic actions, including effects on estrogen and fat metabolism, which may impact the risk of breast and endometrial cancer in women. Exposure to light at night, as it occurs in night shift workers, has been shown to reduce melatonin levels. Evidence for a relationship between melatonin production and cancer risk is accumulating from several more recent nested case-control studies and is further supported by indirect evidence from observational studies of night
Conflicts of interest statement
The authors do not have any conflicts of interest to report with the content of this manuscript.
Acknowledgments
Dr. Viswanathan receives support from NIH Grant 5K07 CA117979-01. Dr. Schernhammer is funded through the NIH CA114534.
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