Light is known to be a potent stimulus for regulating the pineal gland’s production of melatonin and the broader circadian system in humans (11,40–,42). Light not only suppresses nocturnal melatonin secretion but also does so in a characteristic dose–response 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 dose–response 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 α [retinoid Z receptor α] and RZR β [retinoid Z receptor β]). 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.
Researchers at the University of Quebec and the Centre INRS-Institut Armand-Frappier looked at whether working the night shift raised the risk of different cancers in men. Their analysis was based on 3,137 men who had had cancer at one of 11 different sites on their bodies, as well as 512 controls who didn’t have cancer.
Researchers found specifically that working the night shift is linked with a 2.77 times higher risk of prostate cancer, as well as a 1.76 times higher risk of lung cancer, a 2.03 times higher risk of colon cancer, a 1.74 times higher risk of bladder cancer, a 1.31 times higher risk for non-Hodgkin’s lymphoma, a 20.9 times higher risk for rectal cancer and a 2.27 times higher risk for pancreatic cancer.