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  • Oncogenomics
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Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable prognosis

Oncogene volume 25, pages 3479–3488 (2006)Cite this article

Abstract

The canonical Wnt signalling pathway plays a key role during embryogenesis and defects in this pathway have been implicated in the pathogenesis of various types of tumours, including breast cancer. The gene for secreted frizzled-related protein 1 (SFRP1) encodes a soluble Wnt antagonist and is located in a chromosomal region (8p22–p12) that is often deleted in breast cancer. In colon, lung, bladder and ovarian cancer SFRP1 expression is frequently inactivated by promoter methylation. We have previously shown that loss of SFRP1 protein expression is a common event in breast tumours that is associated with poor overall survival in patients with early breast cancer. To investigate the cause of SFRP1 loss in breast cancer, we performed mutation, methylation and expression analysis in human primary breast tumours and breast cell lines. No SFRP1 gene mutations were detected. However, promoter methylation of SFRP1 was frequently observed in both primary breast cancer (61%, n=130) and cell lines analysed by methylation-specific polymerase chain reaction (MSP). We found a tight correlation (P<0.001) between methylation and loss of SFRP1 expression in primary breast cancer tissue. SFRP1 expression was restored after treatment of tumour cell lines with the demethylating agent 5-aza-2′-deoxycytidine. Most interestingly, SFRP1 promoter methylation was an independent factor for adverse patient survival in Kaplan–Meier analysis. Our results indicate that promoter hypermethylation is the predominant mechanism of SFRP1 gene silencing in human breast cancer and that SFRP1 gene inactivation in breast cancer is associated with unfavourable prognosis.

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Acknowledgements

The technical assistance of Sonja von Serenyi, Sevim Alkaya and Inge Losen is greatly appreciated. The study was supported by the German Ministry for Education and Research (BMBF Grant 01KW0404) as part of the German Human Genome Project (DHGP) and a grant from the RWTH Aachen (START program).

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Author notes

  1. H An

    Present address: Department of Radiotherapy, Philipps University Marburg, Germany

Authors and Affiliations

  1. Institute of Pathology, University Hospital of the RWTH Aachen, Aachen, Germany

    J Veeck, H An, F Wiesmann, C Huszka, R Knüchel & E Dahl

  2. Department of Gynecology and Obstetrics, Heinrich-Heine University, Düsseldorf, Germany

    D Niederacher & B Betz

  3. Institute of Medical Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany

    E Klopocki

  4. Medical Clinic IV, University Hospital of the RWTH Aachen, Aachen, Germany

    O Galm

  5. Department of Gynecology, Friedrich-Schiller University Jena, Jena, Germany

    O Camara & M Dürst

  6. Institute of Pathology, Charité, Universitätsmedizin Berlin, Berlin, Germany

    G Kristiansen

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  1. J Veeck
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Correspondence to E Dahl.

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Veeck, J., Niederacher, D., An, H. et al. Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable prognosis. Oncogene 25, 3479–3488 (2006). https://doi.org/10.1038/sj.onc.1209386

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