Micropeptide <scp>CIP</scp> 2A‐ <scp>BP</scp> encoded by <scp>LINC</scp> 00665 inhibits triple‐negative breast cancer progression

Abstract TGF ‐β signaling pathway plays a key role in breast cancer metastasis. Recent studies suggest that TGF ‐β regulates tumor progression and invasion not only via transcriptional regulation, but also via translational regulation. Using both bioinformatics and experimental tools, we identified a micropeptide CIP 2A‐ BP encoded by LINC 00665, whose translation was downregulated by TGF ‐β in breast cancer cell lines. Using TNBC cell lines, we showed that TGF ‐β‐activated Smad signaling pathway induced the expression of translation inhibitory protein 4E‐ BP 1, which inhibited eukaryote translation initiation factor elF4E, leading to reduced translation of CIP 2A‐ BP from LINC 00665. CIP 2A‐ BP directly binds tumor oncogene CIP 2A to replace PP 2A's B56γ subunit, thus releasing PP 2A activity, which inhibits PI 3K/ AKT / NF κB pathway, resulting in decreased expression levels of MMP ‐2, MMP ‐9, and Snail. Downregulation of CIP 2A‐ BP in TNBC patients was significantly associated with metastasis and poor overall survival. In the MMTV ‐Py MT model, either introducing CIP 2A‐ BP gene or direct injection of CIP 2A‐ BP micropeptide significantly reduced lung metastases and improved overall survival. In conclusion, we provide evidence that CIP 2A‐ BP is both a prognostic marker and a novel therapeutic target for TNBC .