E. S. Schernhammer, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; F. Laden, F. E. Speizer, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and Department for Environmental Health, Harvard School of Public Health, Boston; W. C. Willett, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and Departments of Epidemiology and Nutrition, Harvard School of Public Health; D. J. Hunter, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and Department of Epidemiology, Harvard School of Public Health, and Harvard Center for Cancer Prevention, Boston; I. Kawachi, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and Department of Health and Social Behavior, Harvard School of Public Health; G. A. Colditz, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and Departments of Epidemiology and Nutrition, Harvard School of Public Health, and Epidemiology Program, Dana-Faber/Harvard Cancer Center, Boston.
Correspondence to: Eva S. Schernhammer, M.D., M.P.H., Channing Laboratory, 181 Longwood Ave., Boston, MA 02115 (e-mail: eva.schernhammer{at}channing.harvard.edu).Reprint requests to: Graham A. Colditz, M.D., D.P.H., Nurses' Health Study, Channing Laboratory, 181 Longwood Ave., Boston, MA 02115.
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ABSTRACT |
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INTRODUCTION |
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Melatonin, the "hormone of the darkness," has only recently gained substantial attention from the scientific community with regard to its potential oncostatic actions and its possible effect on breast cancer risk (310). Melatonin serum levels in humans decrease when people are exposed to light at night (11). Suppressed serum melatonin levels might enhance tumor development (12). Observational studies (2, 1315) are compatible with an effect of melatonin on breast cancer risk, reporting meaningful increases in breast cancer risk among postmenopausal women exposed to shiftwork. Recently, a tumor-promoting effect of light exposure was demonstrated on chemically induced tumors in rodents (16). To date, melatonin has been shown to be oncostatic for a variety of tumor cells in experimental carcinogenesis (1726). The evidence of a relation between melatonin and oncogenesis in humans is conflicting (27), but the majority of reports indicate protective action (28).
Several mechanisms have been hypothesized to explain an association between melatonin and breast cancer. Cohen et al. (29) proposed that loss of pineal function and the resulting decreased melatonin serum levels may increase reproductive hormone levels and, in particular, estradiol levels, thereby increasing the growth and proliferation of hormone-sensitive cells in the breast. More recent research focuses on potential mechanisms through which melatonin is directly oncostatic. Melatonin is believed to have antimitotic activity by affecting directly hormone-dependent proliferation through interaction with nuclear receptors (4). Another explanation is that melatonin increases the expression of the tumor suppressor gene p53 (3). Cells lacking p53 have been shown to be genetically unstable and thus more prone to tumors (30).
Breast cancer is the most common cancer among women in the United States. To date, the relationship between night work and breast cancer risk has not been evaluated in prospective cohort studies. A causal link between the two would be of public health importance, because small changes in shift patterns may create a substantial decrease of disease burden among women.
In this report, we evaluate the relationship between night work, as a surrogate for light exposure at night, and breast cancer risk in a large prospective cohort of premenopausal and postmenopausal women. Our analysis is based on 10 years of follow-up in 78 562 women participating in the Nurses' Health Study.
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SUBJECTS AND METHODS |
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Ascertainment of Night Shift Working Status
In 1988, the study participants were asked how many years in total they had worked rotating night shifts with at least three nights per month in addition to days or evenings in that month. Information on lifetime years worked on rotating night shift was gathered in eight prespecified categories: never, 12, 35, 69, 1014, 1519, 2029, and 30 or more years. Of the 103 613 nurses who responded to the 1988 questionnaire, 85 197 answered the shiftwork question.
Documentation of Breast Cancer and Deaths
Breast cancer cases were defined as having occurred during the period from June 1988 through May 1998. Nurses who reported the occurrence of breast cancer were asked for permission to review their medical records, and breast cancer was confirmed through review of these records. When medical records were unavailable, breast cancer cases were defined as probable and included in the analysis if they were corroborated by an interview or a letter from the subject. Approximately two thirds of the deaths among cohort members were reported to us by next of kin or the postal system in response to follow-up questionnaires. In addition, we searched the National Death Index to identify deaths among the nonrespondents to each 2-year questionnaire; the computerized National Death Index is a highly sensitive method for identifying deaths in this cohort (34). Data on mortality were more than 98% complete (34, 35). For all deaths possibly attributable to breast cancer, we requested permission from family members (subject to state regulation) to review the medical records. Breast cancer was considered to be the cause of death if the medical records or autopsy report confirmed a fatal breast cancer, if the breast cancer was listed as the underlying cause of death without another, more plausible cause, and if the nurse was known (from hospital records, a family member's report, or another source) to have had breast cancer before death. In no case was the cause listed on the death certificate used as the sole criterion for death due to breast cancer. All interviews and reviews of medical records were conducted by investigators without knowledge of exposure. A total of 2441 case subjects with breast cancer were diagnosed in the base population from June 1988 through May 1998, and pathology records were obtained for 93% of the case subjects. Although these 2441 case subjects included 92 women whose pathology reports had not yet been obtained, we based our analyses on the total, because the accuracy of the self-reporting was extremely high (36). In addition, an analysis limited to case subjects confirmed by pathology reports yielded the same association with night work.
Study Population
A total of 103 613 of the women returned the 1988 questionnaire, which included the question about night work. The population for this study consisted of 85 197 (82.2%) of the respondents who answered the question on night work. Women who did not answer the shiftwork question on the 1988 questionnaire did not differ substantially from respondents in terms of their risk profile (1). We excluded women who reported breast cancer or any other cancer other than nonmelanoma skin cancer on the 1988 questionnaire or any previous questionnaire. A total of 78 562 women remained to form the baseline population for this analysis, and 736 015 person-years of follow-up were accrued from June 1988 through May 1998.
Statistical Analysis
Women were first categorized according to their night work status; the groupings were selected to provide equal 15-year categories: having worked rotating night shifts either never or 114, 1530, or 29 or more years. In some analyses, we collapsed the data into only two categories; in others, we went back to the original eight categories. Information about breast cancer and established risk factors for breast cancer was updated according to the biennial follow-up questionnaire. Information on alcohol consumption was updated every 4 years1986, 1990, and 1994. For each participant, person-months were allocated to categories of years having worked on rotating night shifts, according to the 1988 data. The primary analysis was based on incidence rates, with person-months of follow-up used as the denominator. We used relative risk (RR) as the measure of association; the RR was defined as the incidence rate of breast cancer among women in various categories of years working on rotating night shifts divided by the incidence rate among women who never worked on rotating shifts. MantelHaenszel summary RRs were calculated, adjusting for age in 5-year categories (37). All statistical tests were two-sided. Tests of trends across categories of exposure were calculated by treating the levels of exposure as a continuous, ordinal variable in the regression model. Pooled logistic regression models were used to calculate RRs with adjustment for age, age at menarche (12, 13, and
14 years), age at menopause (
43, 4446, 4749, 5052, 5355, 5658, and >58 years), parity (nulliparous, 12, 34, and
5), age at first birth (<25, 2529, and
30 years), weight change between age 18 years and menopause (<2, 29, 1020, and
20 kg) for menopausal women only, body mass index (weight in kilograms divided by the square of the height in meters) at age 18 years in five categories (<21, 2122.9, 2324.9, 2528.9, and
29 kg/m2), current alcohol consumption (nondrinkers <90 and
90 g/week), height in eight categories (
150, 151155, 156160, 161165, 166170, 171175, 176180, and >180 cm), oral contraceptive use (ever/never), use of postmenopausal hormones (never, past user <5 years, past user
5 years, current user <5 years, and current user
5 years), menopausal status, benign breast disease (yes/no), and family history of breast cancer (yes/no). For all factors, indicator variables were created for missing values and included in the analyses. With short intervals between questionnaires and the low rate of events, this approach yields results similar to those of a Cox regression analysis with time-varying covariates (38).
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RESULTS |
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We attempted to explain the slight differences in the association of shiftwork duration and breast cancer risk between premenopausal and postmenopausal women by examining whether the effects of shiftwork varied in specific subgroups. Because hormone receptor-positive tumors are more likely to be found in older women (39), we examined breast cancers according to their hormonal receptor status and conducted further analyses for premenopausal and postmenopausal women separately. As with total breast cancer, for the estrogen receptor-positive breast cancer case subjects, longer duration in rotating night shifts was associated with a moderate increase in risk, particularly for premenopausal women, and we observed slightly elevated risks with shorter durations of shiftwork. The risk of hormone receptor-negative breast cancer was not elevated after 30 or more years of rotating night shifts (data not shown).
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DISCUSSION |
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Earlier work from Tynes et al. (13) showed an elevated breast cancer risk among postmenopausal radio and telegraph operators exposed to shiftwork. The authors observed no association for women aged 50 years or less but reported an increased breast cancer risk among postmenopausal women more than age 50 years (odds ratio [OR] = 4.3; 95% CI = 0.7 to 26.0) in their small study with 50 case subjects and 259 control subjects. Pukkala et al. (14) found a similar increased incidence of breast cancer among flight attendants (standardized incidence ratio [SIR] = 1.87; 95% CI = 1.15 to 2.23). In a population-based, casecontrol study conducted among 7035 Danish women with breast cancer and their matched control subjects, Hansen (2) estimated an OR of 1.5 (95% CI = 1.2 to 1.7) for breast cancer among women who predominantly worked at night for at least 6 months, after adjustment for socioeconomic status, age at birth of first and last child, and number of children.
Light is known to be a potent stimulus for regulating the pineal gland's production of melatonin and the broader circadian system in humans (11, 4042). Light not only suppresses nocturnal melatonin secretion but also does so in a characteristic doseresponse manner: the brighter the photic stimulus, the greater the suppression of nocturnal melatonin (40). A recent observation among 10 935 visually impaired women (43) underlines a dose-related relationship between visible light and breast cancer risk. The investigators found SIRs for breast cancer of 1.05 (95% CI = 0.84 to 1.3), 0.96 (95% CI = 0.59 to 1.46), 0.79 (95% CI = 0.44 to 1.29), 0.66 (95% CI = 0.24 to 1.44), and 0.47 (95% CI = 0.01 to 2.63) among women with moderate low vision, severe low vision, profound low vision, near-total blindness, and total blindness, respectively. Our own data did not provide sufficient information on intensity of light exposure during night work, but future epidemiologic investigations could define such doseresponse estimates in humans.
Several mechanisms have been hypothesized to explain the association of decreased melatonin levels and increased cancer risk. Although the presence of specific melatonin membrane receptors, MT1 (a high-affinity receptor) and MT2 (a low-affinity receptor), has been demonstrated for some time (44, 45), nuclear receptors also have been found (RZR [retinoid Z receptor
] and RZR
[retinoid Z receptor
]). Only recently, an attempt was successfully undertaken to clarify whether melatonin is able to influence MCF-7 cell proliferation by modulating cell cycle kinetics in MCF-7 human breast cancer cells in vitro (3). Melatonin increases the expression of p53. A receptor interaction with RZR nuclear melatonin receptors may cause an arrest of MCF-7 cells in the G0/G1 phase of the cell cycle pathway that is mediated by the p53 pathway. Such receptor-mediated effects on hormone-dependent cancers had been proposed before, yet these are the first important steps toward clarification. As a potential free-radical scavenger, melatonin may also protect against cancer by shielding DNA from oxidative damage (46). Other recent work (23) suggests that melatonin acts as an immune-modulating agent, since it affects thymic endocrine activity and interleukin 2 by means of metabolic zinc pool turnover in mice. Finally, disturbances in sleep rhythm can directly promote chemically induced liver carcinogenesis in rodents (16). This is the first rodent model in which light-induced circadian clock suppression directly exerted a cancer-promoting effect on the liver.
The results from our study are compatible with a possible oncogenic effect of nighttime light exposure through the melatonin pathway. Although we did not validate self-reported duration of rotating nightshifts, it is likely that our results are accurate, because other self-reports have been highly accurate in this cohort (47), and previous validations of similar questions (e.g., electric blanket use) (48) have shown reasonable reproducibility. Moreover, the prospective design of our study eliminates recall bias. On the other hand, assessment of exposure status with regard to working on rotating night shifts can only be a rough estimate, and misclassification is likely to occur. Since there are more than two comparison groups, even random misclassification may bias the study results in any direction (49). We are concerned that the way we asked for lifetime night work on the 1988 questionnaire may have misled some of the nurses. In the United States, a substantial portion of nurses worked on permanent nightshifts during the period of our investigation (50). These nurses may not have classified themselves as working on rotating shifts, but instead as never-rotating workers, because they may have perceived permanent night work as nonrotating, as opposed to rotating night work. Measurements of melatonin profiles in night workers follow an unidentifiable rhythm and show great variability in the timing of melatonin secretion, thus suggesting that no uniform adaptation of the melatonin rhythm can be achieved in permanent night shift work (51, 52). Because permanent night workers do not completely entrain to their circadian shift rhythm (53), the average serum melatonin levels among these women would be lower than those of never workers. According to the "melatonin hypothesis," which states that certain aspects of modern life, such as light at night, may increase breast cancer risk (12, 54), the permanent night worker would, therefore, be at higher breast cancer risk than a never worker. However, rotating shift workers would still remain at the highest overall risk, because they cannot entrain to their circadian shift rhythm at all and, therefore, would have the lowest melatonin levels. Thus, such misclassification would bias our results toward the null.
Reports about a reduction of plasma melatonin concentration as a general characteristic of healthy aging are conflicting (4, 8, 55, 56). We controlled for age in various ways, but our results did not change substantially in any of these analyses.
Another potential limitation in our study is that women who work more frequently on night shifts may differ from women who do not in a way that influences risk of breast cancer for which we were not able to control. Even though we controlled for known potential confounding factors, there may still be uncontrolled confounding, such as hormone levels, stress, or other differences in lifestyle. Yet whether to treat factors, such as hormone levels or stress, as confounding factors or rather as intermediate factors that represent a step in the causal chain between exposure and disease would need to be considered.
In conclusion, working on rotating night shifts was associated with a moderately increased breast cancer risk among the female nurses in our cohort. The findings from our study, in combination with the results of earlier work, reduce the likelihood that this association is solely due to chance. Since breast cancer constitutes a huge disease burden in the United States and since a substantial portion of workers engage in shiftwork, it will be necessary to further explore the relationship between light exposure and cancer risk through the melatonin pathway.
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NOTES |
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We thank the participants of the Nurses' Health Study for their continuing outstanding dedication to the study and Karen Corsano, Joyce Clifford, and Todd Horowitz for their technical assistance.
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Manuscript received May 8, 2001; revised August 10, 2001; accepted August 16, 2001.
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