Abstract 1047: Circadian disruption induced by light at night upregulates PCNA expression in tissue-isolated human breast cancer xenografts in nude rats

Abstract

Abstract The circadian system and the cell cycle are two global regulatory systems in animals and humans. Previous studies have shown that disruption of either the circadian system or the cell cycle increases the risk of cancer in humans. However, the molecular mechanisms of circadian-mediated cell cycle dysregulation are not completely understood. Because proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and cell cycle regulation, we studied the circadian regulation and disruption of PCNA in an in vivo animal model of human breast cancer. In tissue-isolated ER- MCF-7 human breast cancer xenografts grown in female nude rats exposed to a normal 12L:12D circadian condition, PCNA protein levels were maximal in the morning (2 h after lights on) but remained at very low levels throughout the rest of the 24 h period. To determine whether circadian disruption alters PCNA protein expression, xenograft-bearing nude rats were exposed to low intensity of light at night (LAN) (0.08 μW/cm2). PCNA protein was continuously expressed at a high level throughout the 24 h period in breast cancer xenografts growing in nude rats exposed to the LAN. Exposure of tumor-bearing rats to LAN also resulted in significantly accelerated growth of these xenografts. Moreover, several signaling cascades related to cell growth were examined. Daily rhythms of Akt and MAPK activation in the human breast cancer tumors were disrupted by LAN but did not track the changes in PCNA expression; however, PDK1 activation directly correlated with PCNA expression. Expression of PKCδ and PKCα, downstream targets of PDK1, was differentially elevated by LAN in xenografts in a manner consistent with their reported roles in cell proliferation. In contrast, LAN did not disrupt the rhythmic expression of either PCNA, PKCδ, or PKCα in the liver of the tumor-bearing rats. Expression of insulin-like growth factor 1 receptor (IGF-1R) protein, an upstream signaling molecule for PDK1, also correlated with the expression pattern of PDK1/PKC/PCNA in tumor-bearing rats exposed to LAN. Exposure of tumor-bearing rats to LAN disrupted the circadian rhythm of IGF-1R protein levels in the liver. Finally, circulating IGF-1 concentrations showed circadian disruption in LAN-exposed tumor-bearing nude rats. Thus, interruption of the IGF-1 signaling pathway may constitute a novel molecular mechanism of circadian regulated tumor growth. Taken together, our results suggest that LAN-induced disruption of circadian rhythms in cell signaling cascades accelerates tumor growth in vivo through continuous up-regulation of PCNA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1047.