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Disturbance of circadian gene expression in breast cancer

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Abstract

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 ≥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.

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Acknowledgements

We thank Miss W. L. Chan for editing the manuscript. This study was supported in part by grants from Nation Science Council, Taiwan (NSC93-2314-B-039-006 and NSC93-2314-B-039-028) and a grant from Changhua Christian Hospital, Taiwan.

Conflicts of interest statement

We have no conflicts of interest.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Shou-Jen Kuo, Ming-Feng Hou, Ya-Sian Chang, Nicholas C. Hsu & Jan-Gowth Chang

  2. Institute of Clinical Research, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Shou-Jen Kuo, Ming-Feng Hou, Ya-Sian Chang, Nicholas C. Hsu & Jan-Gowth Chang

  3. Department of Surgery and Pathology, Changhua Christian Hospital, Changhua, Taiwan

    Shou-Jen Kuo, Shou-Tung Chen & Kun-Tu Yeh

  4. Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Ming-Feng Hou

  5. Center for Excellence in Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Jan-Gowth Chang

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  1. Shou-Jen Kuo
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  2. Shou-Tung Chen
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  3. Kun-Tu Yeh
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  4. Ming-Feng Hou
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  5. Ya-Sian Chang
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  7. Jan-Gowth Chang
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Correspondence to Jan-Gowth Chang.

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Supplement Table 1

Polymorphisms of the circadian genes detected in cancerous and adjacent normal tissues of patients with breast cancer (DOC 28 kb)

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Kuo, SJ., Chen, ST., Yeh, KT. et al. Disturbance of circadian gene expression in breast cancer. Virchows Arch 454, 467–474 (2009). https://doi.org/10.1007/s00428-009-0761-7

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  • DOI: https://doi.org/10.1007/s00428-009-0761-7

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