Neutrophil elastase-mediated myoepithelial loss is a therapeutic vulnerability in ductal carcinoma in situ progression.

Progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) marks a critical step in breast cancer progression, yet the mechanisms governing this transition remain poorly defined. Here, we identify neutrophils as a key immunological driver of DCIS progression. Across two independent breast cancer mouse models, neutrophil depletion or genetic deletion of their tumor-derived chemoattractant chitinase-3 like 1 (Chi3l1) preserves the myoepithelial barrier, halts DCIS-to-IDC transition, and suppresses lung metastasis. Mechanistically, tumor-infiltrating neutrophils release neutrophil elastase (NE) that degrades the basement membrane extracellular matrix, leading to erosion of the myoepithelial layer by anoikis. Pharmacological NE inhibition restores myoepithelial integrity and blocks DCIS progression and metastasis. Consistently, elevated NE levels in human breast cancer samples are associated with myoepithelial disruption, DCIS progression, and metastasis. Together, these findings identify neutrophils as key mediators of myoepithelial barrier disruption and highlight NE as a potential therapeutic target for high-risk DCIS.