Circulating melatonin and the risk of breast and endometrial cancer in women

Abstract

Several decades of observational data have accumulated to implicate a potential role for melatonin in cancer prevention. Experimental studies suggest that the antineoplastic action of melatonin arises through many different mechanisms, including melatonin’s antioxidant, antimitotic, and antiangiogenic activity, as well as its ability to modulate the immune system and alter fat metabolism. Melatonin interacts with membrane and nuclear receptors, and may be linked to the regulation of tumor growth. Of particular relevance to breast cancer risk, melatonin may also block the estrogen receptor ERα and impact the enzyme aromatase, which produces estradiol. A growing number of epidemiologic studies have evaluated the relationship between night shift work as well as how varying duration of sleep affects peak melatonin secretion at night. While the studies demonstrate lower nightly melatonin levels in night workers, the evidence for an association between sleep duration and melatonin production is less clear. Similarly, both case-control and prospective cohort studies have consistently linked night shift work with breast cancer risk and, more recently, endometrial cancer – another tumor highly sensitive to estrogens. While, to date, the evidence for an association between sleep duration and breast cancer risk is less convincing, overall, there is increasing support for a potentially important link between melatonin and breast cancer risk and perhaps the risk of other tumors. As evidence increases, modifiable factors that have been shown to affect melatonin production, such as night shift work, are likely to gain increasing recognition as potential public health hazards. Additional studies are needed to delineate further the potential of melatonin in cancer prevention.

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.