Promoter Hyper-methylation of ZNF662 Restrains its Tumor Suppressing Function in Triple-Negative Breast Cancer...

Triple-negative breast cancer (TNBC) has the highest mortality rate among common cancers in women. Thus, the identification of new therapeutic targets is of major significance. Our study identifies ZNF662 as a novel member of KRAB-containing zinc finger proteins (KRAB-ZFPs) family in TNBC. However, its biological function and potential mechanisms in the progression of TNBC have not been clarified. We found that down-regulation of ZNF662 in breast cancer was associated with abnormal promoter methylation. ZNF662 over-expression inhibited triple-negative breast cancer cell proliferation, migration and invasion and induced cell cycle arrest in vitro, and also suppressed the growth and metastasis of xenograft tumors in vivo. Further experiments confirmed that ZNF662 could directly bind to the NGF promoter sites and significantly inhibit NGF transcription activity. In addition, ZNF662 could increase the sensitivity of TNBC cells to the EGFR inhibitor lapatinib. Molecular mechanisms revealed that ZNF662 affected downstream PI3K/AKT and STAT3 signaling pathways to inhibit TNBC progression by down-regulating NGF expression. Altogether, we speculated that ZNF662 might become a promising prognostic marker and therapeutic target for early detection and treatment of TNBC.