The Expression of Notch1 and Notch2 is Up-Regulated on Natural Killer Cells by the Interaction Between NKp46 and Syndecan-1 in a Mouse Breast Cancer Model

BACKGROUND: Breast cancer is characterized by uncontrolled breast cell growth and eventual tumor formation. It is crucial to explore the molecular mechanisms of NK cell function in the breast cancer microenvironment. METHODS: The regulatory factors of Notch1 and Notch2 in NK cells were analyzed in a mouse breast cancer implantation model using flow cytometry, cytotoxicity evaluation, real-time PCR, in vitro co-culture, genetically modified tumor cells, and adoptive transfer of NK cells. RESULTS: Notch1 and Notch2 were differentially expressed on tumor-infiltrating NK cells, forming a Notch1+Notch2+ (DP) subset and Notch1-Notch2-(DN) subset. DP cells expressed higher levels of IFN-γ, TNF-α, granzyme B, perforin, and CD107a upon activation, thereby becoming more cytotoxic. DP cells expressed higher levels of activating receptors, such as NKp46, NKG2D, and DNAM-1. Co-culture with the breast cancer cell line EMT6 up-regulated Notch1 and Notch2. Blockage of the ligation of NKp46 to its ligands prevented the up-regulation of Notch1 and Notch2. Moreover, NK cells expressed lower IFN-γ, TNF-α, Notch1, and Notch2 in Syndecan-1 (an NKp46 co-ligand) knockout EMT6 implants than their counterparts in Syndecan-1-expressing EMT6 implants, and were less competent to inhibit EMT6 implant growth. CONCLUSION: The NKp46-Syndecan-1 interaction promoted Notch1 and Notch2 expression to boost NK cell activity.