Document Type

Article

Disciplines

Medicine and Health Sciences

Abstract

As transcriptional regulators, the genes responsible for maintaining circadian rhythm exert influence in a variety of biological processes. Recently, it has been suggested that the core circadian genes may play a role in breast tumorigenesis, possibly by influencing hormone regulation or other cancer-relevant pathways. Here, we examine the role of the central circadian regulator CLOCK in breast cancer by conducting a genetic and epigenetic association study, as well as transcriptional profiling arrays and a pathway-based network analysis. Significant associations were detected between CLOCK tagging SNPs and breast cancer risk, with apparent effect modification by ER/PR status. Furthermore, hypermethylation in the CLOCK promoter was found to reduce breast cancer risk, and these findings were corroborated by publicly available tissue array data, which showed lower levels of CLOCK expression in healthy controls relative to normal or tumor tissue from breast cancer patients. Finally, we silenced CLOCK in vitro and performed a whole genome expression microarray and pathway analysis, which identified a cancer-relevant network of transcripts with altered expression following CLOCK gene knockdown. These findings support the hypothesis that circadian genes may be relevant for tumorigenesis, and suggest that circadian gene variants may represent a novel panel of breast cancer susceptibility biomarkers.

Comments

Cancer Res. Author manuscript; available in PMC 2011 October 7. Published in final edited form as: Cancer Res. 2010 February 15; 70(4): 1459–1468. Published online 2010 February 2. doi: 10.1158/0008-5472.CAN-09-3798 PMCID: PMC3188957 NIHMSID: NIHMS318135

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