The Core Circadian GeneCryptochrome 2Influences Breast Cancer Risk, Possibly by Mediating Hormone Signaling

Abstract

As transcriptional regulators, circadian genes have the potential to influence a variety of biological pathways, including many cancer-related processes. Cryptochrome 2 (CRY2) is essential for proper circadian timing, and is a key component of the circadian regulatory feedback loop. Here, we report findings from genetic, epigenetic, loss-of-function, and transcriptional profiling analyses of CRY2 in breast cancer. Six SNPs in CRY2 were identified for genotyping in a case-control population (N=441 cases and N=479 controls), and three SNPs (rs11038689, rs7123390, and rs1401417) were significantly associated with postmenopausal breast cancer risk, with significant effect modification by menopausal status (dominant model for rs11038689: odds ratio (OR) = 0.71, 95% confidence interval (CI): 0.51–0.99, P for trend = 0.028; homozygous variants for rs7123390: OR = 0.44, 95% CI: 0.22–0.86, P for trend = 0.028; and rs1401417, OR=0.44, 95% CI: 0.21–0.92, P for trend = 0.017). Interestingly, this association was only evident in women with estrogen and progesterone receptor (ER/PR) negative breast tumors, but not with ER/PR positive tumors. Breast cancer patients also had significantly higher levels of CRY2 promoter methylation relative to controls, which is consistent with tissue array data showing lower levels of CRY2 expression in tumor tissue relative to adjacent normal tissue. Furthermore, in vitro analyses identified a number of breast cancer-relevant genes which displayed altered expression following CRY2 knockdown. These findings suggest a role for CRY2 in breast tumorigenesis, and provide further evidence that the circadian system may be an important modulator of hormone-related cancer susceptibility.

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

“…In the same study, researchers also noted lower expression levels of the CLOCK gene in women free from breast cancer. Conversely, CRY2 shows lower expression levels in breast cancer cells compared with the counterpart normal cells [130]. A positive correlation between expression level of core clock genes and breast cancer risk has been reported for the gene TIMLESS in peripheral blood lymphocytes of 80 breast cancer women compared with age-matched tumor-free equal cases [131].…”

“…The hypo-methylation of promoters and hyper-methylation of the core clock genes, CLOCK and CRY2, are expected to be associated with several breast cancer types [129,130]. The transcriptional deregulation of the clock genes PER1, PER2, and PER3, by CpG site hyper-methylation at the promoter region has been suggested to be related to breast cancer development [177,178].…”

Electric light, particularly at night, disrupts human circadian rhythmicity: is that a problem?

“…Epigenetic changes, including DNA methylation, have recently been identified as important contributors to gene regulation, perhaps accounting for even more of the variability in gene expression than is attributable to structural genetic variations. The epigenetic association analyses of circadian genes and breast cancer further found significantly hypomethylated promoter of CLOCK [79] and hypermethylated promoter of CRY2 [78] in breast cancer cases compared with controls. These detected epigenetic changes are consistent with their expression patterns in breast tumour tissues compared to adjacent normal tissues: high expression level of CLOCK as a putative 'oncogene' and low expression level of CRY2 as a possible 'tumour suppressor'.…”

Relevance of Circadian Rhythm in Cancer

“…For example, in a study of Chinese men, individuals that harbored a SNP in Npas2 had a decreased risk of developing prostate cancer, whereas those with an SNP in Cry2 had nearly double the risk of those that did not [24]. Similarly, other circadian polymorphisms have 1 Relevance of Circadian Rhythm in Cancer been linked to increased postmenopausal breast cancer risk ( Cry2), reduced risk of developing non-Hodgkins lymphoma ( Npas2), increased occurrence and development of non-small cell lung cancer, and increased survival in colorectal and hepatocellular carcinoma ( Clock and Per3, respectively) [25][26][27][28][29][30].…”