Abstract Women harboring germline mutations in BRCA genes have an elevated lifetime risk of breast cancer, with tumors frequently presenting as aggressive, triple-negative basal-like carcinomas. Current preventive strategies rely heavily on prophylactic mastectomy. Existing literature has shown that this malignancy may arise from an aberrant lineage transition, where luminal progenitors lose their identity and differentiate into basal-like cells with oncogenic potential. However, the specific upstream mechanisms which trigger and promote this critical luminal-to-basal switch remain largely unknown. We hypothesized that the immune landscape of the BRCA-deficient mammary gland acts as the stimulus for this pathogenic differentiation. Methods: We utilized a high-dimensional, multi-disciplinary approach to map the ecosystem of early tumorigenesis. To dissect the mechanism, we performed an integrated computational analysis of single-cell RNA sequencing and single-nucleus Multiome (snRNA-seq + snATAC-seq) data derived from a whole-body Brca1-mutant mouse models and organoid cultures. This approach allowed us to map epithelial cell fate changes and dissect the transcriptional and epigenetic consequences of immune interaction, in order to resolve epithelial lineage plasticity under immune pressure. Results: By combining wet-lab with high-resolution multi-omic profiling, we demonstrate that the immune microenvironment dictates epithelial lineage plasticity. Computationally, we resolved a specific, "Pre-tumoral LASP" subpopulation that emerges in the BRCAmut mammary epithelium exclusively upon neutrophil administration. This population is defined by a unique 16-gene signature that drives pathological de-differentiation, including markers of BRCA associated lineage plasticity and epithelial-to-mesenchymal transition drivers. Furthermore, multi-omic integration revealed that the expression of this signature is not random but epigenetically driven. We found significant chromatin accessibility opening at the promoter regions of Fos specifically in the Pre-tumoral LASP cluster. Motif enrichment analysis confirmed these accessible peaks are direct targets of NF-κB, which acts as the master transcriptional switch linking neutrophil exposure to this oncogenic program. This demonstrates that neutrophil-induced NF-κB activity is not only elevated but is positioned to engage newly accessible promoter regions to drive the transcriptional program defining the "Pre-tumoral LASP" population. Disrupting this axis via pharmacological NF-κB inibition demonstrates that this is an NF-κB dependend mechanism. Conclusions: We define a mechanism where neutrophils act as a "switch" for cellular plasticity in BRCA carriers. By epigenetically activating a specific NF-κB-dependent program, neutrophils force luminal progenitors into a transient, highly plastic pre-tumoral state that serves as the cellular origin for basal-like breast cancer. This study suggests that targeting this inflammatory axis offers a promising pharmacological alternative to radical surgery for high-risk patients. Citation Format: Hannah Dewhurst, Camilla Paleari, Arianna Calcinotto, Letizia Boffa. Neutrophils Drive Cancer Initiation in BRCA-Carriers via NF-κB Epigenetic Reprogramming of Luminal Progenitors into Aberrant Basal-Like Cells abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-A009.
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