Stromal peroxidasin drives early tumor growth in breast cancer

Summary The extracellular matrix (ECM) plays multifaceted tumor-promoting and tumor-restraining roles in breast cancer progression. Extracellular peroxidases represent a critical yet underexplored component of stromal remodeling machinery. Peroxidasin (PXDN), an extracellular peroxidase with established roles in collagen IV crosslinking, has been associated with poor outcomes in several cancers, but its role in breast cancer remains unclear. Through temporal proteomic analysis of dysregulated ECM proteins, we identified PXDN as upregulated during early tumor development in mouse models. In human breast cancers, PXDN expression shows compartment-specific associations with patient outcome, with high stromal PXDN, predominantly cancer-associated fibroblast (CAF)-derived, correlating with poor prognosis. We demonstrate that PXDN regulates CAF behavior, with subsequent matrix remodeling affecting cancer cell behavior. Reduction of CAF-derived PXDN in vivo slows tumor development, while pharmacological inhibition of extracellular peroxidases improves overall survival. These findings establish PXDN as a mediator of breast tumor progression and a promising future therapeutic target.