ADAM23 hypermethylation predicts decreased disease‐free survival in low‐risk breast cancer patients

Summary

A disintegrin and metalloprotease 23 (ADAM23), a member of ADAM family, has been involved in neuronal differentiation and cancer. ADAM23 is considered a possible tumor suppressor gene and is frequently down‐regulated in various types of malignancies. Its epigenetic silencing through promoter hypermethylation was observed in breast cancer (BC). In this study, we evaluated a prognostic significance of ADAM23 promoter methylation for hematogenous spread and disease‐free survival (DFS).

Pyrosequencing was used to quantify ADAM23 methylation in tumors of 203 BC patients. Presence of circulating tumor cells (CTCs) in their peripheral blood was detected by quantitative reverse transcription PCR. Expression of epithelial (KRT19) or mesenchymal (EMT‐inducing transcription factors TWIST1, SNAI1, SLUG and ZEB1) mRNA transcripts was interrogated in CD45‐depleted peripheral blood mononuclear cells.

ADAM23 methylation was significantly lower in tumors of patients with the mesenchymal CTCs (P=0.006). It positively correlated with Ki‐67 proliferation, especially in mesenchymal CTC negative patients (P=0.001). In low‐risk patients, characterized by low Ki‐67 and mesenchymal CTC absence, ADAM23 hypermethylation was an independent predictor of DFS (P=0.006).

Our results indicate that ADAM23 is likely involved in BC progression and dissemination of mesenchymal CTCs. ADAM23 methylation has potential to serve as a novel prognostic marker and therapeutic target.

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