The m6A reader IGF2BP3 promotes triple-negative breast cancer metastasis through HOXB9-IL15RA pathway

Triple-negative breast cancer (TNBC) is among the most life-threatening women malignancies with largely uncharacterized pathogenic mechanisms. While N6-methyladenosine (m6A) methylation has been documented to impact carcinogenesis through extensively altering the gene expression profile, its precise role in TNBC remains poorly understood. Here, we found that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) promotes TNBC progression in an m6A modification-dependent way. Mechanistically, IGF2BP3 binds to and stabilizes the mRNA of a transcription factor, HOXB9, which subsequently licenses the expression of interleukin 15 receptor α subunit (IL-15RA). The IL-15/IL15RA signaling thus potentiates the migration and invasion of neoplastic cells and contributes to in vivo metastasis of TNBC. These observations provide novel insights into the role of RNA modification in the occurrence of TNBC, and demonstrate the applicability of targeting the m6A machinery especially specific reader proteins in the clinical treatment of advanced TNBC.