1959

Circadian disruption associated with shift work is associated with increased risk of colon and breast cancer. Light at night is one aspect of shift work which is a possible cause for increased cancer risk. Light at night suppresses nocturnal melatonin, a negative growth factor, thereby, accelerating cancer growth. Light also has non-melatonin mediated effects upon central and peripheral circadian clocks. Clock genes coordinate circadian rhythms through an auto-regulatory feed back loop by action of positive elements (BMAL-1:CLOCK dimers) binding to E boxes of the negative regulatory elements (PER, CRY genes) to regulate gene expression in a time-lagged fashion throughout the day. Tumors have beating clocks characterized by circadian rhythmic BMAL-1 protein nuclear translocation which coordinates tumor growth rate, cell division, and mitosis through clock controlled protein expression (vascular endothelial growth factor, VEGF, thymidylate synthase, WEE1). C3HeB/FeJ female mice with transplanted mammary tumors on a 12hr light:12 hr dark (LD) schedule, housed singly, maintain normal circadian rhythms in voluntary wheeling running activity. In LD the amplitude of circadian rhythm in wheel running activity correlates inversely with tumor growth rates. Acutely switching these tumor bearing mice to constant light (LL) exposure (light at night, 300 lux at cage level)induces immediate partial disruption of host circadian rhythm in locomotor activity, suppressing the circadian amplitude of activity and decreasing overall mean activity levels. LL abolishes the relationship between circadian wheel running amplitude and tumor growth and is associated with an instantaneous doubling of tumor growth. Tumor growth acceleration by LL is not explained by changes in estrous cycling, body weight, or food intake. Tumors from light exposed mice have higher mitotic index, and greater immunohistochemically detectable VEGF and epidermal growth factor receptor-1. Tumors from mice exposed to constant light show a decrease in total cell and nuclear PER1, BMAL1 and CLOCK circadian clock protein content, with no change in PER2 or WEE1 protein. The tumor accelerating effect of LL could be diminished by housing tumor bearing mice 4/cage. In summary, host circadian coordination modulates tumor growth rates under normal lighting conditions, disruption of host circadian coordination through constant light results in accelerated tumor growth along with altered tumor clock protein content and nuclear translocation and increase cancer cell proliferation. These tumor accelerating effects of constant light are to some extent, behaviorally avoidable.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]