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Background  We have previously reported that expression of the Wnt antagonist genes  SFRP1  and  SFRP5  is frequently silenced by promoter hypermethylation in breast cancer. SFRP2 is a further Wnt inhibitor whose expression was recently found being downregulated in various malignancies. Here we investigated whether SFRP2 is also implicated in human breast cancer, and if so whether  SFRP2  promoter methylation might serve as a potential tumor biomarker.    Methods  We analyzed  SFRP2  mRNA expression and  SFRP2  promoter methylation in 10 breast cell lines, 199 primary breast carcinomas, 20 matched normal breast tissues and 17 cancer-unrelated normal breast tissues using RT-PCR, realtime PCR, methylation-specific PCR and Pyrosequencing, respectively. SFRP2 protein expression was assessed by immunohistochemistry on a tissue microarray. Proliferation assays after transfection with an  SFRP2  expression vector were performed with mammary MCF10A cells. Statistical evaluations were accomplished with SPSS 14.0 software.    Results  Of the cancerous breast cell lines, 7/8 (88%) lacked  SFRP2  mRNA expression due to  SFRP2  promoter methylation ( P  < 0.001).  SFRP2  expression was substantially restored in most breast cell lines after treatment with 5-aza-2'-deoxycytidine and trichostatin A. In primary breast carcinomas SFRP2 protein expression was strongly reduced in 93 of 125 specimens (74%).  SFRP2  promoter methylation was detected in 165/199 primary carcinomas (83%) whereas all cancer-related and unrelated normal breast tissues were not affected by  SFRP2  methylation.  SFRP2  methylation was not associated with clinicopathological factors or clinical patient outcome. However, loss of SFRP2 protein expression showed a weak association with unfavorable patient overall survival ( P  = 0.071). Forced expression of  SFRP2  in mammary MCF10A cells substantially inhibited proliferation rates ( P  = 0.045).    Conclusion  The  SFRP2  gene is a high-frequent target of epigenetic inactivation in human breast cancer. Its methylation leads to abrogation of  SFRP2  expression, conferring a growth advantage to epithelial mammary cells. This altogether supports a tumor suppressive function of  SFRP2 . Although clinical patient outcome was not associated with  SFRP2  methylation, the high frequency of this epimutation and its putative specificity to neoplastic cells may qualify  SFRP2  promoter methylation as a potential candidate screening marker helping to improve early breast cancer detection.

Promoter hypermethylation of the SFRP2 gene is a high-frequent alteration and tumor-specific epigenetic marker in human breast cancer