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. 2020 Jan 2;39(1):e102190.
doi: 10.15252/embj.2019102190. Epub 2019 Nov 22.

Micropeptide CIP2A-BP Encoded by LINC00665 Inhibits Triple-Negative Breast Cancer Progression

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Free PMC article

Micropeptide CIP2A-BP Encoded by LINC00665 Inhibits Triple-Negative Breast Cancer Progression

Binbin Guo et al. EMBO J. .
Free PMC article

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 CIP2A-BP encoded by LINC00665, 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-BP1, which inhibited eukaryote translation initiation factor elF4E, leading to reduced translation of CIP2A-BP from LINC00665. CIP2A-BP directly binds tumor oncogene CIP2A to replace PP2A's B56γ subunit, thus releasing PP2A activity, which inhibits PI3K/AKT/NFκB pathway, resulting in decreased expression levels of MMP-2, MMP-9, and Snail. Downregulation of CIP2A-BP in TNBC patients was significantly associated with metastasis and poor overall survival. In the MMTV-PyMT model, either introducing CIP2A-BP gene or direct injection of CIP2A-BP micropeptide significantly reduced lung metastases and improved overall survival. In conclusion, we provide evidence that CIP2A-BP is both a prognostic marker and a novel therapeutic target for TNBC.

Keywords: TNBC; CIP2A-BP; PI3K/AKT/NFκB pathways; invasion and metastasis.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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