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.