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Down-regulation of CXCL12 mRNA expression by promoter hypermethylation and its association with metastatic progression in human breast carcinomas

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Abstract

Purpose

Not only is the expression of CXCR4 on breast cancers a key determinant of tumor metastasis, CXCL12 exhibiting peak levels of constitutive expression in organs representing the first destinations of cancer metastasis, but is proposed to be also essential for the organ-specific metastatic process.

Methods

In this study, the expressions of CXCR4 and CXCL12 were investigated using quantitative RT-PCR and immunohistochemistry in samples of 63 primary breast carcinomas and 20 normal breast tissues. Using methylation-specific PCR, we also analyzed the methylation status of CXCL12.

Results

Both up-regulation of CXCR4 and down-regulation of CXCL12 were observed in primary breast carcinomas. Over-expression of CXCR4 mRNA was significantly related to lymph node metastasis status and strong Her-2 expression, while decreased expression of CXCL12 mRNA was significantly associated with positive lymph node metastasis and estrogen receptor negativity. Methylation-specific PCR showed that 52.4% of breast tumors were hypermethylated in the CXCL12 promoter region. The expression levels of DNA methyltransferase (DNMT) 1 and DNMT3B were significantly higher in the CXCL12-methylated breast carcinomas than in the CXCL12-unmethylated ones.

Conclusions

In summary, DNA hypermethylation of CXCL12 plays an important role in the down-regulation of CXCL12 expression in breast carcinomas. Cancer cells lacking expression of CXCL12, but maintaining over-expression of CXCR4, can selectively spread to target organs in which the ligand is highly secreted.

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Abbreviations

CT :

Threshold cycle

CXCR4:

CXC chemokine receptor-4

CXCL12:

CXC chemokine ligand-12

DNMT:

DNA methyltransferase

ER:

Estrogen receptor

GPCR:

G-protein coupled receptor

MSP:

Methylation-specific polymerase chain reaction

PR:

Progesterone receptor

SDF-1:

Stromal cell-derived factor-1

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Acknowledgments

We thank the staff of the Breast Cancer Center, Shandong Cancer Hospital and Institute for assistance in patient care and specimen collection. Written consent for publication was obtained from the patients or their relatives. Support was provided by the Natural Science Foundation of Shandong, 2006ZRC03115 and Y2005C39. This study was also supported by the National High Technology Research and Development Program of China (863 Program), 2007AA02Z437.

Conflict of interest statement

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Shandong University School of Medicine, Wenhua Xi Road, Jinan, Shandong, 250012, People’s Republic of China

    Wei Zhou

  2. Shandong Cancer Hospital and Institute, Jiyan Road 440#, Jinan, Shandong Province, 250117, People’s Republic of China

    Wei Zhou, Ningbo Liu, Fenghua Xu, Yanbing Liu, Weixia Zhong, Xianrang Song, Xiuli Zhang, Guangsheng Wei & Jinming Yu

  3. Department of Neurosurgery, Qilu Hospital, Shandong University, Wenhua Xi Road, Jinan, Shandong, 250012, People’s Republic of China

    Zheng Jiang

  4. Department of Immunology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jingshi Road, Jinan, Shandong, 250062, People’s Republic of China

    Peie Wen

  5. Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, Jingshi Road, Jinan, Shandong, 250062, People’s Republic of China

    Xiaotian Chang

Authors
  1. Wei Zhou
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  2. Zheng Jiang
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  3. Ningbo Liu
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  9. Xiaotian Chang
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  10. Xiuli Zhang
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  11. Guangsheng Wei
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  12. Jinming Yu
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Corresponding author

Correspondence to Jinming Yu.

Additional information

Wei Zhou and Zheng Jiang contributed equally to this work.

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Zhou, W., Jiang, Z., Liu, N. et al. Down-regulation of CXCL12 mRNA expression by promoter hypermethylation and its association with metastatic progression in human breast carcinomas. J Cancer Res Clin Oncol 135, 91–102 (2009). https://doi.org/10.1007/s00432-008-0435-x

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  • DOI: https://doi.org/10.1007/s00432-008-0435-x

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