title: Chronically Alternating Light Cycles Increase Breast Cancer Risk in Mice.
abstract: Although epidemiological studies in shift workers and flight attendants have associated chronic circadian rhythm disturbance (CRD) with increased breast cancer risk, causal evidence for this association is lacking. Several scenarios have been proposed to contribute to the shift work-cancer connection: (1) internal desynchronization, (2) light at night (resulting in melatonin suppression), (3) sleep disruption, (4) lifestyle disturbances, and (5) decreased vitamin D levels due to lack of sunlight. The confounders inherent in human field studies are less problematic in animal studies, which are therefore a good approach to assess the causal relation between circadian disturbance and cancer. However, the experimental conditions of many of these animal studies were far from the reality of human shift workers. For example, some involved xenografts (addressing tumor growth rather than cancer initiation and/or progression), chemically induced tumor models, or continuous bright light exposure, which can lead to suppression of circadian rhythmicity. Here, we have exposed breast cancer-prone p53(R270H/+)WAPCre conditional mutant mice (in a FVB genetic background) to chronic CRD by subjecting them to a weekly alternating light-dark (LD) cycle throughout their life. Animals exposed to the weekly LD inversions showed a decrease in tumor suppression. In addition, these animals showed an increase in body weight. Importantly, this study provides the first experimental proof that CRD increases breast cancer development. Finally, our data suggest internal desynchronization and sleep disturbance as mechanisms linking shift work with cancer development and obesity.
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720 BA, the Netherlands; Department of Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, Rotterdam 3000 CA, the Netherlands.
authors.forename: Kirsten C G
authors.initials: KC
authors.lastname: Van Dycke
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720 BA, the Netherlands.
authors.forename: Wendy
authors.initials: W
authors.lastname: Rodenburg
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720 BA, the Netherlands.
authors.forename: Conny T M
authors.initials: CT
authors.lastname: van Oostrom
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720 BA, the Netherlands.
authors.forename: Linda W M
authors.initials: LW
authors.lastname: van Kerkhof
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720 BA, the Netherlands.
authors.forename: Jeroen L A
authors.initials: JL
authors.lastname: Pennings
authors.affiliation: Institute for Medical Psychology, Ludwig-Maximilian University, Munich 80336, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Roenneberg
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720 BA, the Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. Electronic address: harry.van.steeg@rivm.nl.
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.affiliation: Department of Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, Rotterdam 3000 CA, the Netherlands. Electronic address: g.vanderhorst@erasmusmc.nl.
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
mesh_terms: D000818:Animals; D001835:Body Weight / Q000528:radiation effects; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D003430:Cross-Sectional Studies; D005260:Female; D008137:Longitudinal Studies; D051379:Mice; D008817:Mice, Mutant Strains; D017440:Photoperiod; D012307:Risk Factors; D020178:Sleep Disorders, Circadian Rhythm / Q000150:complications* / Q000209:etiology