Calpain 2 Isoform-Specific Cleavage of Filamin A Enhances HIF1α Nuclear Translocation, Promoting Metastasis in Triple-Negative Breast Cancer.

Overview

abstract

Triple-negative breast cancer (TNBC) remains a challenge due to its aggressive nature and limited therapeutic options. Calpain 2, a member of the calcium-dependent cysteine protease family, is particularly associated with poor prognosis in TNBC. This study explores the isoform-specific role of calpain 2 in TNBC, examining its correlation with prognosis and its mechanistic impact on metastasis. Bioinformatic analyses, including Kaplan-Meier survival plots, univariate Cox proportional analysis, and gene set enrichment analysis (GSEA), assessed CAPN2 expression and its association with mesenchymal genes in TNBC. Results of cell-based experiments with CAPN2 knockdown or overexpression indicate that elevated CAPN2 expression correlates with poor clinical outcomes and enhanced metastatic potential in TNBC. CAPN2 knockdown inhibited the epithelial-mesenchymal transition (EMT), reducing cancer cell proliferation, migration, and invasion. Calpain 2 downregulation reversed the EMT by reducing isoform-specific cleavage of filamin A, HIF1α nuclear localization and TWIST1 transcription. CNa 29, a calpain 2-specific inhibitor, reduced cancer cell proliferation, decreased filamin A cleavage, downregulated TWIST1 expression, and significantly retarded metastasis,. In conclusion, calpain 2 plays a critical role in TNBC progression by modulating HIF1α and TWIST1, to promote the EMT and metastasis. Isoform-selective inhibition of calpain 2 with CNa 29 presents a promising therapeutic strategy for managing TNBC.