Frequent methylation of genes encoding wnt pathway antagonists: Secreted frizzled-related protein 1 and dickkopf 3 in invasive breast cancer

Introduction: Wnt signaling pathway is often dysregulated in the pathogenesis of various malignancies, including breast cancer. This might be related to methylation of the genes encoding antagonists of this signaling pathway. Aim: The aim of the study was to analyze the methylation status of the promoter regions of Wnt antagonists-secreted frizzled-related protein 1 (sFRP1) and Dickkopf 3 (DKK3) and to determine their correlation with clinicopathological parameters and survival outcome in patients with primary invasive ductal breast cancer. Materials and Methods: The methylation status of sFRP1 and DKK3 was analyzed in 160 breast tumor samples using methylation-specific polymerase chain reaction. Statistical analysis was performed using SPSS software. P ≤ 0.05 was considered as statistically significant. Results: The promoter region of sFRP1 and DKK3 genes was found to be methylated in 76% and 64% of total invasive ductal breast cancer patients, respectively. The promoter methylation in sFRP1 and DKK3 genes was significantly associated with larger tumor size, positive lymph nodes, advanced stage, and perinodal extension of breast tumors. Further, sFRP1 methylation was associated with human epidermal growth factor receptor 2-positive tumors while DKK3 methylation was associated with Grade 3 tumors. Survival analysis demonstrated that sFRP1 methylation was correlated with reduced overall survival in breast cancer patients. Conclusion: Promoter methylation of Wnt pathway antagonists is frequent in breast cancer ultimately leading to probable upregulation of the pathway in these tumors. Hence, sFRP1 and DKK3 methylation may be used as a valuable biomarker in clinical breast cancer management.