Disturbance of circadian gene expression in breast cancer.

To explore the mechanism of the disruption of circadian rhythm in breast cancer, we examined the expression of nine circadian genes in 53 newly diagnosed breast cancers by immunohistochemical staining, mutational analysis, and methylation analysis of the promoter of circadian genes. Our results showed that 37 of the 53 breast cancer tissues had hypermethylation on the promoters of PER1, PER2, CRY1, or BMAL1. Twenty-five out of 53 paired noncancerous (normal) tissues had methylation on the promoter of PER1 or CRY1. Our results indicated a higher frequency of concurrent methylation of PER1 and CRY1 promoters in cancerous and normal tissues. Promoter methylation of the PER1 correlates with c-erbB2 immunohistochemical reaction of > or = 2+ (p = 0.012) and has a strong inverse correlation with estrogen receptor positivity (p = 0.016). We further analyzed the patterns of circadian gene expression by immunohistochemical methods and found that homogeneous expression of PER2 or BMAL1 is significantly associated with lymph node metastasis and poor prognosis. PER2 heterogeneous expression correlates with <2+ c-erbB2 immunohistochemical reaction. Heterogeneous expression of CLOCK is associated significantly with 3-year survival. In conclusion, the expression pattern of circadian genes might be a biomarker for the prognosis of breast cancer.