Abstract PS3-12-11: Neutrophil elastase promotes myoepithelial layer dissolution and breast cancer progression

Abstract Breast cancer progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) is a critical transition that underlies the development of metastatic disease. DCIS now accounts for ∼20% of all breast cancer diagnoses due to early screening; however, only about half of these cases will progress to IDC. Despite this, there are currently no biomarkers to identify high-risk DCIS, leading to widespread over-treatment. A defining hallmark that distinguishes DCIS from IDC is the presence of an intact myoepithelial cell layer, which physically restrains tumor invasion. Disrupting this layer is a requirement for breast cancer progression but remains a poorly understood process. Elucidating mechanisms of myoepithelial disruption is crucial to identify targetable biomarkers of DCIS progression and improve treatment of early breast cancer. Neutrophils are prominent pro-tumorigenic immune cells associated with poor outcomes and resistance to therapy. While elevated neutrophil levels have been reported in DCIS patient samples, their functional role in early progression remains unknown. In this study, we demonstrate that neutrophil depletion in breast cancer Genetically Engineered Mouse Models (GEMMs) results in striking retention of the myoepithelial layer and halts DCIS transition to IDC. Similarly, genetic ablation of the secreted protein Chitinase-3 like 1 (Chi3l1), a key neutrophil chemoattractant, phenocopies neutrophil depletion in two independent GEMMs and inhibits DCIS progression. In contrast, Chi3l1 overexpression leads to increased neutrophil infiltration, accelerated myoepithelial layer loss, and enhanced lung metastasis, a phenotype reversed by neutrophil depletion. Furthermore, elevated neutrophil levels in human DCIS samples also correlated with significant disruption of the myoepithelium. Mechanistically, we identify neutrophil elastase (NE) as a major effector: NE is secreted by tumor-infiltrating neutrophils and directly promotes myoepithelial layer dissolution. Pharmacological inhibition of NE preserves the myoepithelial barrier and significantly impairs DCIS progression. Despite the fact that only 50% of DCIS cases progress to IDC, the lack of predictive markers has led to widespread over-treatment. Our results reveal a novel immunological mechanism driving myoepithelial layer disruption and highlight neutrophils and NE as potential biomarkers and therapeutic targets for DCIS progression. These findings could help stratify DCIS patients for treatment based on neutrophil activity or NE expression, reducing over-treatment while targeting high-risk cases. Given the availability of NE inhibitors, our work offers a translationally actionable framework for preventing invasive breast cancer. Citation Format: T. Taifour, Y. Gu, A. Massé, V. Sanguin-Gendreau, D. Zuo, B. Xiao, S. Attalla, W. Muller. Neutrophil elastase promotes myoepithelial layer dissolution and breast cancer progression [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-12-11.