Epigenetic silencing of ADAMTS18 promotes cell migration and invasion of breast cancer through AKT and NF‐ κ B signaling

ADAMTS 18 dysregulation plays an important role in many disease processes including cancer. We previously found ADAMTS 18 as frequently methylated tumor suppressor gene ( TSG ) for multiple carcinomas, however, its biological functions and underlying molecular mechanisms in breast carcinogenesis remain unknown. Here, we found that ADAMTS 18 was silenced or downregulated in breast cancer cell lines. ADAMTS 18 was reduced in primary breast tumor tissues as compared with their adjacent noncancer tissues. ADAMTS 18 promoter methylation was detected in 70.8% of tumor tissues by methylation‐specific PCR , but none of the normal tissues. Demethylation treatment restored ADAMTS 18 expression in silenced breast cell lines. Ectopic expression of ADAMTS 18 in breast tumor cells resulted in inhibition of cell migration and invasion. Nude mouse model further confirmed that ADAMTS 18 suppressed breast cancer metastasis in vivo. Further mechanistic studies showed that ADAMTS 18 suppressed epithelial‐mesenchymal transition ( EMT ), further inhibited migration and invasion of breast cancer cells. ADAMT 18 deregulated AKT and NF ‐ κ B signaling, through inhibiting phosphorylation levels of AKT and p65. Thus, ADAMTS 18 as an antimetastatic tumor suppressor antagonizes AKT and NF ‐ κ B signaling in breast tumorigenesis. Its methylation could be a potential tumor biomarker for breast cancer.