Mechanical cues from the extracellular matrix (ECM) regulate various cellular processes in cell proliferation, migration and differentiation via distinct mechanotransduction pathways. In breast cancer patients, increase in tumor tissue stiffness is correlated with distant metastasis and poor outcome. Previous studies show that, cell invasion and metastasis. Using 3D reconstituted extracellular matrixes that recapitulate the range of physiological stiffness from normal mammary glands to breast tumors, we previously reported that increased ECM stiffness promotes Epithelial-Mesenchymal Transition (EMT) and identified the TWIST1 transcription factor as a key player driving EMT and invasion in response to increasing ECM stiffness. High ECM stiffness activates the LYN tyrosine kinase, which phosphorylates TWIST1 and promotes TWIST1 to enter the nucleus, thus triggering EMT and invasion. To understand how LYN is activated at high ECM stiffness, we performed an unbiased screen for tyrosine phosphatases that is required for high stiffness-induced EMT and invasion in basal-subtype mammary cells. This screen identified a novel role of protein tyrosine phosphatase epsilon (PTPRE) in TWIST1/LYN mechanotransduction. We show that genetic deletion of PTPRE blocked high ECM stiffness-induced EMT and invasion in human and mouse TNBC cell-derived acini as well as in patient-derived triple-negative breast cancer (TNBC) organoids, demonstrating a conserved role of PTPRE in stiffness-induced invasion. Mechanistically, knockdown or pharmacological inhibition of PTPRE blocks LYN activation, TWIST1 nuclear translocation and EMT at high stiffness. Biochemical analyses and AlphaFold modeling suggest that PTPRE bind to LYN and dephosphorylates Tyr507 to activate the LYN kinase. Functionally, treatment of mice carrying TNBC PDX tumors with a PTPRE inhibitor decreased local invasion and lung metastasis. This study identifies a novel role for PTPRE in matrix-stiffness induced EMT and metastasis in TNBC and broadens the repertoire of actionable targets implicated in breast cancer metastasis. The importance of mechanical force and tissue stiffness in regulating breast cancer invasion and metastasis has only recently been appreciated. This study raises the promise to target novel mechanotransduction pathways and mechanoregulators to combat breast tumor invasion and metastasis.