Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers.
Disruption of circadian rhythm may be a risk factor in the development of breast cancer, but molecular changes in circadian rhythm controlled genes in breast cancer cells are still unexplored. We used immunohistochemical staining, methylation specific PCR and direct sequencing methods to analyze molecular changes in three most important genes, namely PER1, PER2 and PER3, in circadian rhythm in 55 cases of breast cancer of Taiwanese women. Our results reveal disturbances in the expression of the three period (PER) genes in most (>95%) of the breast cancerous cells in comparison with the nearby non-cancerous cells. The PER gene deregulation is not caused by genetic mutations but most probably by methylation of the PER1 or PER2 promoter. Methylation of the PER gene promoters has a strong correlation with c-erbB2 expression (P = 0.017). Since the circadian clock controls expression of cell-cycle related genes, we suggest that disturbances in PER gene expression may result in disruption of the control of the normal circadian clock, thus benefiting the survival of cancer cells and promoting carcinogenesis. Differential expression of circadian genes in non-cancerous and cancerous cells may provide a molecular basis for chronotherapy of breast cancer.
Chen
Shou-Tung
ST
Department of Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
Choo
Kong-Bung
KB
Hou
Ming-Feng
MF
Yeh
Kun-Tu
KT
Kuo
Shou-Jen
SJ
Chang
Jan-Gowth
JG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D018797:Cell Cycle Proteins; D002470:Cell Survival; D002940:Circadian Rhythm; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis*; D056950:Period Circadian Proteins; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D012307:Risk Factors; D013624:Taiwan; D014157:Transcription Factors / Q000096:biosynthesis*
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; C539022:PER1 protein, human; C421902:PER2 protein, human; C512644:PER3 protein, human; C539023:Per1 protein, mouse; C512645:Per3 protein, mouse