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.