A novel micropeptide miPEP205 suppresses the growth and metastasis of TNBC.

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and poses a treatment challenge due to high recurrence risk. Consequently, there is an urgent need for novel and efficacious therapies targeting TNBC. In this context, our study delineates the identification and characterization of a long non-coding RNA (lncRNA)-derived micropeptide miPEP205. Notably, the micropeptide exerts a significant inhibitory effect on the growth and metastasis of TNBC. Moreover, we observed a substantial down-regulation of micropeptide expression in clinical samples, which was markedly associated with a poor prognosis. Mechanistically, our research demonstrated that EGR3 governs lncRNA MIR205HG and the micropeptide expression, while miPEP205 boosts GSK-3β phosphorylation at Tyr216. This cascade causes β-catenin degradation, deactivating the GSK-3β/β-catenin signaling pathway and ultimately inhibits TNBC progression. Remarkably, our experiments in the spontaneous breast cancer mice model MMTV-PyMT demonstrated that the introduction of the miPEP205 gene or exogenous administration of the micropeptide miPEP205 significantly curtailed tumor growth and lung metastasis, and enhanced the overall survival among tumor-bearing mice. In conclusion, our study uncovers a previously uncharacterized micropeptide derived from a lncRNA, showcasing potent antitumor properties. These findings position miPEP205 as a promising novel target for therapeutic intervention in TNBC.