Light-at-night, circadian disruption and breast cancer: assessment of existing evidence
01 Aug 2009-International Journal of Epidemiology (Oxford University Press)-Vol. 38, Iss: 4, pp 963-970
TL;DR: If a consensus eventually emerges that LAN does increase risk, then the mechanisms for the effect are important to elucidate for intervention and mitigation and will provide for the development of lighting technologies at home and at work that minimize circadian disruption, while maintaining visual efficiency and aesthetics.
Abstract: Background Breast cancer incidence is increasing globally for largely unknown reasons. The possibility that a portion of the breast cancer burden might be explained by the introduction and increasing use of electricity to light the night was suggested >20 years ago.
Methods The theory is based on nocturnal light-induced disruption of circadian rhythms, notably reduction of melatonin synthesis. It has formed the basis for a series of predictions including that non-day shift work would increase risk, blind women would be at lower risk, long sleep duration would lower risk and community nighttime light level would co-distribute with breast cancer incidence on the population level.
Results Accumulation of epidemiological evidence has accelerated in recent years, reflected in an International Agency for Research on Cancer (IARC) classification of shift work as a probable human carcinogen (2A). There is also a strong rodent model in support of the light-at-night (LAN) idea.
Conclusion If a consensus eventually emerges that LAN does increase risk, then the mechanisms for the effect are important to elucidate for intervention and mitigation. The basic understanding of phototransduction for the circadian system, and of the molecular genetics of circadian rhythm generation are both advancing rapidly, and will provide for the development of lighting technologies at home and at work that minimize circadian disruption, while maintaining visual efficiency and aesthetics. In the interim, there are strategies now available to reduce the potential for circadian disruption, which include extending the daily dark period, appreciate nocturnal awakening in the dark, using dim red light for nighttime necessities, and unless recommended by a physician, not taking melatonin tablets.
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...The precise mechanisms of cancer prevention remain to be elucidated (Stevens, 2009)....
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TL;DR: A framework that focuses on the cross‐factoring of the ways in which artificial lighting alters natural light regimes (spatially, temporally, and spectrally), and the ways that light influences biological systems, particularly the distinction between light as a resource and light as an information source is proposed.
Abstract: The ecological impacts of nighttime light pollution have been a longstanding source of concern, accentuated by realized and projected growth in electrical lighting. As human communities and lighting technologies develop, artificial light increasingly modifies natural light regimes by encroaching on dark refuges in space, in time, and across wavelengths. A wide variety of ecological implications of artificial light have been identified. However, the primary research to date is largely focused on the disruptive influence of nighttime light on higher vertebrates, and while comprehensive reviews have been compiled along taxonomic lines and within specific research domains, the subject is in need of synthesis within a common mechanistic framework. Here we propose such a framework that focuses on the cross-factoring of the ways in which artificial lighting alters natural light regimes (spatially, temporally, and spectrally), and the ways in which light influences biological systems, particularly the distinction between light as a resource and light as an information source. We review the evidence for each of the combinations of this cross-factoring. As artificial lighting alters natural patterns of light in space, time and across wavelengths, natural patterns of resource use and information flows may be disrupted, with downstream effects to the structure and function of ecosystems. This review highlights: (i) the potential influence of nighttime lighting at all levels of biological organisation (from cell to ecosystem); (ii) the significant impact that even low levels of nighttime light pollution can have; and (iii) the existence of major research gaps, particularly in terms of the impacts of light at population and ecosystem levels, identification of intensity thresholds, and the spatial extent of impacts in the vicinity of artificial lights.
706 citations
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...Exposure to light at night has been shown to disrupt the circadian cycle of hormone production in humans, particularly melatonin, which has been linked to an increase in cancer risk in shift-workers (Stevens, 1987, 2009; Megdal et al., 2005; Reiter et al., 2011)....
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TL;DR: Findings on shift work, in relation to risks of CVD, metabolic syndrome and diabetes are also suggestive but not conclusive for an adverse relationship, making it difficult to draw general conclusions.
Abstract: Background Shift work, including night work, has been hypothesized to increase the risk of chronic diseases, including cancer, cardiovascular disease (CVD), metabolic syndrome and diabetes. Recent reviews of evidence relating to these hypotheses have focussed on specific diseases or potential mechanisms, but no general summary of the current data on shift work and chronic disease has been published.
Methods Systematic and critical reviews and recent original studies indexed in PubMed prior to 31 December 2009 were retrieved, aided by manual searches of reference lists. The main conclusions from reviews and principle results from recent studies are presented in text and tables.
Results Published evidence is suggestive but not conclusive for an adverse association between night work and breast cancer but limited and inconsistent for cancers at other sites and all cancers combined. Findings on shift work, in relation to risks of CVD, metabolic syndrome and diabetes are also suggestive but not conclusive for an adverse relationship.
Conclusions Heterogeneity of study exposures and outcomes and emphasis on positive but non-significant results make it difficult to draw general conclusions. Further data are needed for additional disease endpoints and study populations.
514 citations
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...responsible for the rise in breast cancer incidence seen in the industrialized world [3]....
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...As seen, circadian disruption is also induced by light exposure at night and light at night is becoming a public health issue (Pauley, 2004; Stevens, 2009)....
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...It has also been concluded that ‘shift work that involves circadian disruption is probably carcinogenic to humans’ (Straif et al., 2007) and can lead to higher incidence of cardiovascular disease and obesity (Karlsson et al., 2001; Stevens, 2009)....
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References
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95 citations
TL;DR: A new short-period circadian mutant, part-time (prtm), which is caused by a loss-of-function mutation in the Cryptochrome1 (Cry1) gene, and a long- period circadian mutant named Overtime (Ovtm), are described.
Abstract: In animals, circadian behavior can be analyzed as an integrated system, beginning with genes and leading ultimately to behavioral outputs. In the last decade, the molecular mechanism of circadian clocks has been unraveled primarily by the use of phenotype-driven (forward) genetic analysis in a number of model systems. Circadian oscillations are generated by a set of genes forming a transcriptional autoregulatory feedback loop. In mammals, there is a “core” set of circadian genes that form the primary negative feedback loop of the clock mechanism (Clock/Npas2, Bmal1, Per1, Per2, Cry1, Cry2, and CK1e). A further dozen candidate genes have been identified and have additional roles in the circadian gene network such as the feedback loop involving Rev-erbα. Despite this remarkable progress, it is clear that a significant number of genes that strongly influence and regulate circadian rhythms in mammals remain to be discovered and identified. As part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen using a wide range of nervous system and behavioral phenotypes, we have identified a number of new circadian mutants in mice. Here, we describe a new short-period circadian mutant, part-time (prtm), which is caused by a lossof-function mutation in the Cryptochrome1 (Cry1) gene. We also describe a long-period circadian mutant named Overtime (Ovtm). Positional cloning and genetic complementation reveal that Ovtm is encoded by the F-box protein FBXL3, a component of the SKP1–CUL1–F-box protein (SCF) E3 ubiquitin ligase complex. The Ovtm mutation causes an isoleucine to threonine (I364T) substitution leading to a loss of function in FBXL3 that interacts specifically with the CRYPTOCHROME (CRY) proteins. In Ovtm mice, expression of the PERIOD proteins PER1 and PER2 is reduced; however, the CRY proteins CRY1 and CRY2 are unchanged. The loss of FBXL3 function leads to a stabilization of the CRY proteins, which in turn leads to a global transcriptional repression of the Per and Cry genes. Thus, Fbxl3 Ovtm defines a molecular link between CRY turnover and CLOCK/BMAL1-dependent circadian transcription to modulate circadian period.
91 citations
TL;DR: The results of this study suggest that increasing sleep duration is modestly associated with an increased breast cancer risk, and short duration of sleep (<7 h/night) is not substantially associated with increased risk.
Abstract: One important function of sleep may be its contribution to the maintenance of the immune system and regulation of the circadian rhythms by melatonin. Researchers have speculated that disruption of immune functions involving cortisol levels and natural killer cell activity may increase breast cancer risk whereas increased melatonin exposure may protect against breast cancer. We conducted a multistate population-based case-control study of 4,033 women with invasive breast cancer and 5,314 community women without breast cancer in which we inquired about women's sleep habits in the recent past and during adult lifetime. Relative to women who slept 7.0-7.9 h/night, the multivariate odds ratio for developing breast cancer among women who slept an average of 9 h or more per night approximately 2 years prior to interview was 1.13 (95% CI 0.93-1.37). The multivariate-adjusted odds ratio for the continuous term was 1.06 (95% CI 1.01-1.11), suggesting a 6% increase in risk for every additional hour of sleep. Similar patterns were observed for average lifetime adult sleep duration. We found little evidence that sleeping few hours per night was associated with breast cancer risk. The results of this study suggest that increasing sleep duration is modestly associated with an increased breast cancer risk. In contrast, short duration of sleep (<7 h/night) is not substantially associated with increased risk. Further research in this area is warranted.
89 citations
TL;DR: The timing of anthracycline, platinum, and fluoropyrimidine-based drug therapies during the 24h is relevant to the toxic–therapeutic ratio of these agents in the treatment of gynecologic and genitourinary cancers.
Abstract: The circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, tumor control, and host survival. Optimally timed cancer chemotherapy with doxorubicin or pirarubicin (06:00h) and cisplatin (18:00h) enhanced the control of advanced ovarian cancer while minimizing side effects, and increased the response rate in metastatic endometrial cancer. Therapy of metastatic bladder cancer with doxorubicin-cisplatin was made more tolerable by this same circadian approach resulting in a 57% objective response rate. This optimally timed therapy is also effective in the adjuvant setting, decreasing the expected frequency of metastasis from locally advanced bladder cancer. Circadian fluorodeoxyuridine (FUDR) continuous infusion (70% of the daily dose given between 15:00h and 21:00h) has been shown effective for metastatic renal cell carcinoma resulting in 29% objective response and stable disease of more than 1 yr duration in the majority of patients. Toxicity is reduced markedly when FUDR infusion is modulated to circadian rhythms. In a multicenter trial in patients with metastatic renal cell cancer, patients were randomized to a flat or a circadian-modified FUDR infusion. This study confirmed a significant difference in toxicity and dose intensity, favoring the circadian-modified group. Hormone refractory metastatic prostate cancer has been treated with circadian-timed FUDR chemotherapy; however, without objective response. Biological agents such as interferon-alpha and IL-2 have shown low but effective disease control in metastatic renal cell cancer, however, with much toxicity. Each of these cytokines shows circadian stage dependent toxicity and efficacy in model systems. In summary, the timing of anthracycline, platinum, and fluoropyrimidine-based drug therapies during the 24h is relevant to the toxic therapeutic ratio of these agents in the treatment of gynecologic and genitourinary cancers.
89 citations
TL;DR: Mathematical models show that the therapeutic index of chemotherapeutic drugs can be optimized through distinct delivery profiles, depending on the initial host/tumor status and variability in circadian entrainment and/or cell cycle length.
Abstract: The circadian clock orchestrates cellular functions over 24 hours, including cell divisions, a process that results from the cell cycle. The circadian clock and cell cycle interact at the level of genes, proteins, and biochemical signals. The disruption or the reinforcement of the host circadian timing system, respectively, accelerates or slows down cancer growth through modifications of host and tumor circadian clocks. Thus, cancer cells not only display mutations of cell cycle genes but also exhibit severe defects in clock gene expression levels or 24-hour patterns, which can in turn favor abnormal proliferation. Most of the experimental research actively ongoing in this field has been driven by the original demonstration that cancer patients with poor circadian rhythms had poor quality of life and poor survival outcome independently of known prognostic factors. Further basic research on the gender dependencies in circadian properties is now warranted, because a large clinical trial has revealed that gender can largely affect the survival outcome of cancer patients on chronotherapeutic delivery. Mathematical models further show that the therapeutic index of chemotherapeutic drugs can be optimized through distinct delivery profiles, depending on the initial host/tumor status and variability in circadian entrainment and/or cell cycle length. Clinical trials and systems-biology approaches in cancer chronotherapeutics raise novel issues to be addressed experimentally in the field of biological clocks. The challenge ahead is to therapeutically harness the circadian timing system to concurrently improve quality of life and down-regulate malignant growth.
87 citations