Light at Night Activates IGF-1R/PDK1 Signaling and Accelerates Tumor Growth in Human Breast Cancer Xenografts

Abstract

Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, including humans. However, the molecular mechanisms by which diurnal and circadian rhythms regulate cell proliferation are relatively poorly understood. In this study, we report that tumor growth in nude rats bearing human steroid receptor-negative MCF-7 breast tumors can be significantly accelerated by exposing the rats to light at night (LAN). Under normal conditions of an alternating light/dark cycle, proliferating cell nuclear antigen (PCNA) levels in tumors were maximal in the early light phase but remained at very low levels throughout the daily 24-hour cycle period monitored. Surprisingly, PCNA was expressed in tumors continually at a high level throughout the entire 24-hour period in LAN-exposed nude rats. Daily fluctuations of Akt and mitogen activated protein kinase activation in tumors were also disrupted by LAN. These fluctuations did not track with PCNA changes, but we found that activation of the Akt stimulatory kinase phosphoinositide-dependent protein kinase 1 (PDK1) directly correlated with PCNA levels. Expression of insulin-like growth factor 1 receptor (IGF-1R), an upstream signaling molecule for PDK1, also correlated with fluctuations of PDK1/PCNA in the LAN group. In addition, circulating IGF-1 concentrations were elevated in LAN-exposed tumor-bearing nude rats. Finally, RNAimediated knockdown of PDK1 led to a reduction in PCNA expression and cell proliferation in vitro and tumor growth in vivo, indicating that PDK1 regulates breast cancer growth in a manner correlated with PCNA expression. Taken together, our findings demonstrate that LAN exposure can accelerate tumor growth in vivo, in part through continuous activation of IGF-1R/PDK1 signaling. Cancer Res; 71(7); 2622-31. Ó2011 AACR.

Entrainment of breast (cancer) epithelial cells detects distinct circadian oscillation patterns for clock and hormone receptor genes

“…36 This observation is further supported by animal studies showing that mammary tumors grow more rapidly, and overall survival decreases, in rodents subjected either to constant light or constant darkness. 37,38 In this report, we discuss for the first time that entrainment of human mammary epithelial cells in culture represents an additional strategy that takes into account the biological time component to advance breast cancer research. Based on the observation that rhythmic expression of core circadian genes is observed in most peripheral tissues 39 and can be induced in cultured fibroblasts by serum shock, 31 we set out to test whether serum-shocked cultured human mammary epithelial cells display an autonomous functional inner clock.…”

Artificial light-at-night – a novel lifestyle risk factor for metabolic disorder and cancer morbidity

“…In nude rats, accelerated growth of MCF-7 human breast cancer xenografts has been noted in response to constant ALAN exposure compared with the counterpart rats kept under normal alternating light-dark cycle [144,158]. In support of this finding, ALAN exposure as low as 0.2 lux has been demonstrated to be sufficient to induce tumor growth and increase tumor lipid uptake and metabolism [159].…”

“…ALAN exposure as a prevailing feature of our modern 24/7 (h/days) active society is recognized as the most powerful factor, behind circadian disruption [138-140; Figure 2]. The evidence for a causal and direct association between ALAN-induced circadian disruption and breast cancer development comes primarily from both epidemiological observations [141][142][143] and experimental studies [144][145][146].…”

Does Current Scientific Evidence Support a Link between Light at Night and Breast Cancer among Female Night-Shift Nurses? Review of Evidence and Implications for Occupational and Environmental Health Nurses

“…Research demonstrates that exposure to LAN can accelerate tumor growth in vivo (Blask, Dauchy, Sauer, Krause, & Brainard, 2003;Wu et al, 2011). Studies have demonstrated that rodent exposure to as little as 0.2 lux of LAN can disrupt host circadian rhythms in non-tumor-bearing rats and stimulate the metabolism and proliferation of human cancer xenografts in rats (Dauchy et al, 2010;Dauchy, Sauer, Blask, & Vaughan, 1997).…”