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  • Oncogenomics
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CLCA2 tumour suppressor gene in 1p31 is epigenetically regulated in breast cancer

Oncogene volume 23, pages 1474–1480 (2004)Cite this article

Abstract

The calcium-activated chloride channel gene family is clustered in the 1p31 region, which is frequently deleted in sporadic breast cancer. Recent studies have indicated the association of the second member of this gene family (CLCA2) with the development of breast cancer and metastasis. We have now shown the absence of expression of CLCA2 in several breast cancer tumours and cell lines, which confirms the results from other reports. When overexpressed in CLCA2-negative cell lines, their tumorigenicity and metastasis capability were significantly reduced, suggesting a tumour suppressor role for CLCA2 in breast cancer. The mechanisms behind the silencing of CLCA2 in breast cancer, however, have not been elucidated to date. Although we were able to identify CLCA2 mutations in breast cancers, somatic mutations are not the major cause of CLCA2 gene silencing. On the other hand, treatment of breast cancer CLCA2-negative cell lines with demethylating agents was able to restore CLCA2 expression, suggesting an epigenetic inactivation of this gene. Bisulphite-sequencing of the promoter-associated CpG island of the CLCA2 gene in breast tumours demonstrated that the absence of expression in these tumours was caused by hypermethylation of the promoter CpG island. In contrast, in breast cancer cell lines, tumours, and control cell lines that express CLCA2, a much lower level, and often absence, of methylation of the promoter were demonstrated. These findings demonstrate that CLCA2 is frequently inactivated in breast cancer by promoter region hypermethylation, which makes it an excellent candidate for the 1p31 breast cancer tumour suppressor gene.

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Acknowledgements

We thank Dr Harold Asch for kindly providing the breast tumour samples; Natacha Diaz Meyer for helpful input; Michelle Detwiller, MS and Shakeeba Waseh, BS for their technical assistance. This work was supported in part by a grant (DAMD17-98-1-8294) from the United States Department of Defense (to JKC), by an Institutional Research Grant (IRG-02-197-01) from the American Cancer Society (to KSA), by a Cancer Center Support Grant (CA16056) from the National Cancer Institute (to Roswell Park Cancer Institute).

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  1. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, 14263, NY, USA

    Xiurong Li, John K Cowell & Khalid Sossey-Alaoui

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  1. Xiurong Li
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Correspondence to Khalid Sossey-Alaoui.

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Li, X., Cowell, J. & Sossey-Alaoui, K. CLCA2 tumour suppressor gene in 1p31 is epigenetically regulated in breast cancer. Oncogene 23, 1474–1480 (2004). https://doi.org/10.1038/sj.onc.1207249

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