Carcinogenesis Advance Access originally published online on March 24, 2005
Carcinogenesis 2005 26(7):1241-1246; doi:10.1093/carcin/bgi075
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Carcinogenesis vol.26 no.7 © Oxford University Press 2005; all rights reserved.
Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers
1 Department of Molecular Medicine, China Medical University Hospital, Taichung, Taiwan, 2 Departments of Surgery and Pathology, Changhua Christian Hospital, Changhua, Taiwan, 3 Department of Medical Research Education Taipei Veterans General Hospital, Shih-Pai, Taipei, Taiwan, 4 Department of Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan and 5 Taipei Institute of Pathology, Taipei, Taiwan
* To whom correspondence should be addressed at: Department of Molecular Medicine, China Medical University Hospital, 2, Yuh Der Road, Taichung, Taiwan. Tel: +886 4 22052121 ext. 7075; Fax: +886 4 22033295; Email: d6781{at}www.cmuh.org.tw
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.
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