In this prospective investigation of sleep duration and breast cancer among Chinese women in Singapore, we found a significant decline in postmenopausal breast cancer risk with increasing self-reported hours of sleep. The inverse association was noted mainly in lean (less than or equal to the median BMI of 23.2) women, especially those free of a history of diabetes. It is noteworthy that in the same study population, we observed a significant trend of increasing urinary melatonin levels with increasing sleep duration. Thus, our data are compatible with the notion that modifications in melatonin as a result of variation in sleep duration may play a role in breast cancer development.
Our results show an inverse association between duration of sleep and breast cancer risk in postmenopausal women but there is no evidence that sleep duration is associated with premenopausal breast cancer risk. However, the lower age limit of this cohort study is 45 years and only 26% of the female cohort participants and 140 incident cases of breast cancer were between the ages of 45–50 years. Therefore, the present study cannot meaningfully address the question of whether menopausal status modifies the association between sleep duration. Our overall results on sleep duration and breast cancer risk are compatible with findings from a Finnish cohort study (9
). In the Finnish study, sleep duration reported in 1975 was used to predict breast cancer from 1976 to 1996. Compared with those with 7–8 h of sleep, women who reported 9+ h showed a 31% risk reduction that was not statistically significant. A significant risk reduction (RR of 0.28) associated with 9+ h of sleep was reported in an analysis that was restricted to women who reported the same sleep duration in both 1975 and 1981. It is of interest that average BMI was 22.7 for women in the Finnish study, not unlike the average BMI of women in the Singapore Chinese Health Study. In contrast, our results differed from those reported in two studies conducted in the USA (10
); the average BMI of participants in these two studies was ~25.0. One was a large population-based case–control study conducted in Massachusetts, New Hampshire and Wisconsin; sleep duration was positively associated with breast cancer risk. Relative to women whose average lifetime sleep hours per night were 7.0–7.9 h, breast cancer risk was below unity for women who reported sleeping <7 h per night and was above unity for those who reported sleeping 8+ h per night (10
). In the Nurses' Health Study, sleep duration reported in 1986 was not associated with breast cancer risk (11
). Compared with women sleeping 7 h/day, the risk for those sleeping ≤5, 6, 8 and 9+ h were 0.93, 0.98, 1.05 and 0.95, respectively. BMI was adjusted for in both USA studies but it is not known whether results on sleep duration and risk were modified by body size.
Previous studies have found that night/shift workers tend to excrete less melatonin in urine than day workers (27
); this difference in melatonin levels has been hypothesized to explain, in part, the higher breast cancer risk found in studies of female night/shift workers and flight attendants (6
). Sleep pattern probably influences breast cancer risk via the same melatonin-mediated pathway. In the present study, urinary melatonin levels exhibited a statistically significant, dose-dependent positive association with self-reported number of hours of sleep. Postmenopausal women reporting 9+ h of sleep possessed urinary melatonin levels that were 42% higher than those reporting ≤6 h of sleep (); this association was apparent primarily in leaner women whose BMI was below the median (). In a cross-sectional analysis conducted in the Nurses' Health Study, urinary melatonin levels were 52% higher among women with 9+ h of sleep compared with those with ≤5 h of sleep after adjusting for BMI and other covariates but it is not known whether body weight modified this association (28
There is accumulating evidence that the impact of menopausal hormones, history of diabetes and other hormone-related breast cancer risk factors may be modified by body size and that leaner women may be most affected (25
). The inverse association between sleep duration and postmenopausal breast cancer risk was most evident in lean women who were free of a history of diabetes; this is compatible with the hypothesis that melatonin's protective effect on the breast may be mediated through an estrogen-related pathway (2
). High circulating estrogen is a recognized risk factor for breast cancer (24
) and high melatonin levels have been linked to low circulating estrogen in women (33
), although these results are not all consistent (28
). Leaner, and especially non-diabetic, postmenopausal women are known to possess lower levels of circulating estrogen and lower risk for breast cancer than their heavier counterparts (24
). Therefore, if the melatonin–breast cancer link is at least partly tied to the estrogen–breast cancer pathway and the quantitative estrogen–risk relationship is a non-linear one, then one would predict that any observed melatonin–breast cancer association would be most apparent among women with the lowest levels of endogenous estrogen.
Results from our cross-sectional study on urinary melatonin levels in Singapore Chinese add to the sparse data in Asian populations, particularly from population-based samples. Studies conducted in different populations may be informative because of the differences in baseline estrogen profiles, body size and other lifestyle habits and these factors may influence melatonin levels. Consistent with many previous studies conducted in primarily Western populations (34
), we observed a significant decline in melatonin levels with increasing age. We also noted that independent of age and time of urine collection, Singapore Chinese men possessed 22% higher levels of urinary melatonin than women. Overall, the literature on melatonin levels between men and women, based mainly on Caucasian data, does not suggest any consistent differences by gender (34
). In the present study, the higher levels noted in men are consistently observed in each age group and each category of specimen collection time between 8 a.m. and 4 p.m.. It is unlikely that this observed gender effect is an artifact. We believe the consistent positive association between melatonin levels and sleep hours in both men and women strengthens the overall observation and demonstrates the utility of this single measurement of melatonin using a spot urine specimen.
Strengths of this study include its prospective design that minimizes recall bias of sleep duration. Information on relevant covariates allows us to adjust for important potential confounders during statistical analysis of study data. Finally, demonstration of a significant positive association between sleep hours and melatonin levels in our study population, in both men and women, provides a biologically sound explanation for our observed sleep duration–breast cancer risk association. A major limitation of the present study is the lack of information on sleep pattern at multiple time points and about lighting conditions during sleep, leading to non-differential misclassification of exposure status in study subjects. Since it is established that such non-differential errors tend to result in a diminution of RR estimates (35
), our observed risk reduction in breast cancer risk associated with longer hours of sleep may be an underestimation of the underlying association. We did not have information on work history of rotating shift work. To our knowledge, this is the first study in an Asian population that examines the role of sleep duration–melatonin and breast cancer risk. Our findings provide further indirect support that circadian disruption may be etiologically related to breast cancer and may contribute to the rising incidence of breast cancer in newly affluent societies throughout Asia (18
). This study represents the strongest evidence to date of an ‘environmental’ link to the rapidly increasing breast cancer incidence in Singapore and elsewhere in Asia.