A disintegrin and metalloprotease 23 hypermethylation predicts decreased disease‐free survival in low‐risk breast cancer patients

Abstract

A Disintegrin And Metalloprotease 23 ( ADAM23), a member of the ADAM family, is involved in neuronal differentiation and cancer. ADAM23 is considered a possible tumor suppressor gene and is frequently downregulated in various types of malignancies. Its epigenetic silencing through promoter hypermethylation was observed in breast cancer ( BC). In the present study, we evaluated the 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 ( CTC) in their peripheral blood was detected by quantitative RT‐ PCR. Expression of epithelial ( KRT19 ) or mesenchymal ( epithelial‐mesenchymal transition [EMT]‐inducing transcription factors TWIST1 , SNAI1 , SLUG and ZEB1 ) mRNA transcripts was examined in CD45‐depleted peripheral blood mononuclear cells. ADAM23 methylation was significantly lower in tumors of patients with the mesenchymal CTC ( P =  .006). It positively correlated with Ki‐67 proliferation, especially in mesenchymal CTC‐negative patients ( P =  .001). In low‐risk patients, characterized by low Ki‐67 and mesenchymal CTC absence, ADAM23 hypermethylation was an independent predictor of DFS ( P =  .006). Our results indicate that ADAM23 is likely involved in BC progression and dissemination of mesenchymal CTC. ADAM23 methylation has the potential to function as a novel prognostic marker and therapeutic target.