Breast Cancer Cell–Derived Soluble CD44 Promotes Tumor Progression by Triggering Macrophage IL1β Production

IL1β is a central regulator of systemic inflammatory response in breast cancer, but the precise regulatory mechanisms that dictate the overproduction of IL1β are largely unsolved. Here, we show that IL1β secretion is increased by the coculture of human monocyte-like cells and triple-negative breast cancer (TNBC) cells. In addition, macrophages robustly produced IL1β when exposed to the conditioned media of TNBC cells. Consistent with these observations, macrophage depletion decreased serum IL1β and reduced breast cancer progression in an orthotopic breast cancer mouse model. Profiling the secretome of human breast cancer cells revealed that the CD44 antigen was the most differentially released protein in basal conditions of TNBC cells. Antibody-mediated neutralization of CD44 abrogated IL1β production in macrophages and inhibited the growth of primary tumors. These results suggest IL1β-mediated oncogenic signaling is triggered by breast cancer cell membrane-derived soluble CD44 (sCD44) antigen, and targeting sCD44 antigen may provide an alternative therapeutic strategy for breast cancer treatment by modulating inflammatory tumor microenvironment. SIGNIFICANCE: A novel positive feedback loop between IL1β and CD44 promotes TNBC malignant progression.