Downregulation of PIEZO1 Activity Promotes Breast Cancer Cell Survival under Shear Stress by Modulating β-Catenin and BCL2

Tumor cells encounter diverse mechanical forces during cancer progression, and the mechanosensitive ion channel PIEZO1 governs how breast cancer cells adapt to these cues, thereby shaping their metastatic potential. Analysis of clinical datasets revealed differential regulation of PIEZO1 between primary and metastatic breast cancers. In this study, we demonstrate that PIEZO1 regulates the proliferation, migration, and survival of breast cancer cells in a mechanosensitive environment-dependent manner. Under static conditions, optimal PIEZO1 activity is required for both proliferation and migration, which is mediated by metalloproteinases, RHOA, and S100A4. Although optimal PIEZO1 activity is required for sustained proliferation and migratory capacity, loss of PIEZO1 confers a survival advantage in triple-negative breast cancer cells under mechanically challenging conditions similar to those encountered in circulation. This phenotype was largely associated with context-specific modulation of survival pathways, including β-catenin, pERK1/2, and BCL2, indicating a mechanoenvironment-mediated rewiring of survival pathways. Chemosensitivity assays further revealed that although PIEZO1 silencing sensitized the breast cancer cells to doxorubicin in static conditions, it enhanced drug resistance in anoikis-inducing conditions. Together, these findings uncover a dual, stage-specific role for PIEZO1 in breast cancer, in which optimal PIEZO1 activity sustains proliferation and invasion, whereas PIEZO1 loss enhances cell survival under mechanostress, thereby potentiating metastatic dissemination. These results highlight PIEZO1 as a mechanosensitive protein in breast cancer, and therapeutic modulation of PIEZO1 should consider the breast cancer subtype and mechanical microenvironment for optimal therapeutic outcomes. SIGNIFICANCE: Breast cancer cells encounter diverse mechanical forces during tumor progression and metastasis. We show that although optimal PIEZO1 activity supports growth and invasion at the primary site, its loss enhances survival and drug resistance under shear stress and anchorage-independent conditions, suggesting PIEZO1 as a stage-specific mechanotherapeutic target in breast cancer.