Abstract 3314: RIPK2 promotes metastatic behavior in inflammatory breast cancer and is an attractive therapeutic target

Abstract Inflammatory breast cancer (IBC) is a rare but aggressive type of breast cancer characterized by early and rapid metastasis leading to poor clinical outcomes. The tumor microenvironment (TME), including immune cells, fibroblasts and endothelial cells, has emerged as a major regulator of IBC aggressiveness, however little is known about how IBC cells may orchestrate this pro-tumorigenic milieu. Inflammatory pathways such as NF-kB, concomitant with cytokine-induced signalling, are upregulated in IBC; however, the mechanisms underpinning these pathways are poorly understood. Receptor Interacting Protein Kinase 2 (RIPK2) mediates nucleotide-binding oligomerization domain (NOD) cell signaling that has been shown to activate NF-kB and to mediate chronic inflammation in a variety of diseases. Herein, we demonstrate that RIPK2 mediates the metastatic behavior in IBC by regulating NF-kB signaling and cytokine production. Specifically, using gain and loss of function strategies, including shRNAs, CRISPR gene editing and a small molecule inhibitor, we show that RIPK2 promotes an inflammatory transcriptome in IBC cells leading to the secretion of factors such as IL-8, IL-6 and Activin-A. As a corollary, RIPK2 enhances key IBC phenotypes, including angiogenic potential, emboli (sphere) formation, 3D invasion, a hybrid-EMT phenotype and metastatic growth in the lung. Collectively, we provide pioneering evidence that RIPK2 regulates the pro-inflammatory phenotype of IBC cells, making it an attractive target for the treatment of this disease. Citation Format: Innocent Ojobile, Alaa Zare, John M. Githaka, Einav Renert, Lynne-Marie Postovit. RIPK2 promotes metastatic behavior in inflammatory breast cancer and is an attractive therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3314.