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.

Histone deacetylase inhibitors induce the expression of tumor suppressor genes Per1 and Per2 in human gastric cancer cells

“…The maintenance of the molecular mechanism of the circadian clockwork has a profound influence on human health, and its alteration has frequently been associated with multiple diseases, including cancer (7)(8)(9)(10)(11)(12). Several in vivo and in vitro studies suggest that, in addition to their main role within the molecular mechanism of the circadian clock, Period circadian regulator (Per)1 and Per2 genes can also function as tumor suppressors due to their involvement in cell proliferation, apoptosis, cell cycle control, and DNA damage response (13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

Association between PER3 length polymorphism and onco-hematological diseases and its influences on fatigue on awakening in patients

“…Several studies have reported circadian alterations in cancer patients and tumor-bearing animals [4,5] . Moreover, current data have suggested that this disruption could be more than a consequence of cancer development and it may act as a risk factor [6,7] . In 2007, the International Agency for Research on Cancer (IARC, World Health Organization) concluded that shiftwork that involves circadian disruption is probably carcinogenic to humans (Group 2A) [8] .…”

Melatonin-induced KiSS1 expression inhibits triple-negative breast cancer cell invasiveness

“…As a disruption of light cycles increases the risk of breast cancer (13,47,48), it is plausible that melatonin and KiSS1 may exhibit similar expression patterns in breast cancer. Melatonin has been revealed to regulate circadian rhythms by inhibiting KiSS1 expression in the brain of rodents (27).…”

“…Breast cancer is frequently identified in women, and demonstrates high mortality once metastasized (9)(10)(11). Patients with breast cancer present with low levels of melatonin, which may be due to disruptions of the circadian rhythm (4,(12)(13)(14)(15). Melatonin treatment has been suggested to halt breast cancer progression and improve quality of life in patients with breast cancer (16,17).…”