Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Cancer Res. 2010 Feb 15;70(4):1459-68. doi: 10.1158/0008-5472.CAN-09-3798. Epub 2010 Feb 2.
The transcription factors responsible for maintaining circadian rhythm influence 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 pathways relevant to cancer. To evaluate this hypothesis, we conducted a genetic and epigenetic association study, as well as a transcriptional profiling array and a pathway-based network analysis. We report significant correlations between single nucleotide polymorphisms associated with the central circadian regulator CLOCK and breast cancer risk, with apparent effect modification by estrogen receptor/progesterone receptor status. We also found that hypermethylation in the CLOCK promoter reduced the risk of breast cancer, and lower levels of CLOCK expression were documented in healthy controls relative to normal or tumor tissue from patients with breast cancer. 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. Our findings support the hypothesis that circadian genes influence tumorigenesis, and identify a set of circadian gene variants as candidate breast cancer susceptibility biomarkers.
负责维持生物钟节律的转录因子影响着多种生物过程。最近有研究表明，核心生物钟基因可能在乳腺癌发生中发挥作用，可能通过影响激素调节或其他与癌症相关的途径。为了评估这一假说，我们进行了遗传和表观遗传关联研究、转录谱分析和基于通路的网络分析。我们报告了与中央生物钟调节剂 CLOCK 相关的单核苷酸多态性与乳腺癌风险之间存在显著相关性，雌激素受体/孕激素受体状态的明显影响修饰。我们还发现，CLOCK 启动子的高甲基化降低了乳腺癌的风险，并且与健康对照相比，CLOCK 表达水平在正常或来自乳腺癌患者的肿瘤组织中较低。最后，我们在体外沉默了 CLOCK，并进行了全基因组表达微阵列和通路分析，该分析确定了一组在 CLOCK 基因敲低后表达发生改变的与癌症相关的转录本网络。我们的研究结果支持了生物钟基因影响肿瘤发生的假说，并确定了一组生物钟基因变异作为候选乳腺癌易感性生物标志物。
