PROJECT SUMMARY Metastatic breast cancer is driven by pro-tumor immune responses. No immuno-agents are currently approved for use in breast cancer and the ability of these agents to mitigate disease is currently unclear. Consequently, developing a clear understanding of the mechanisms by which immune cells are regulated during breast cancer progression is critical for the successful application of immunotherapy for breast cancer. We propose to evaluate a protein kinase called Hormonally-upregulated Neu-associated Kinase (HUNK), a tumor and metastasis promoting factor, as a target that alters immune response in metastatic breast cancer. Immune cells called tumor associated macrophages (TAMs) are recruited to the tumor microenvironment through paracrine signaling with tumor cells, which results in an immune suppressive phenotype and metastatic progression. Previous studies show that TAMs exhibit an “alternatively” activated phenotype consistent with M2-type polarization and identify IL-4 as a major cytokine that induces the M2-phenotype. We provide evidence that HUNK regulates IL-4 production in mammary tumor cells, which results in a reduction in TAMs in the tumor microenvironment. We hypothesize that HUNK regulates IL-4 production in mammary tumor cells, which in turn, drives alternative activation of macrophages (ie presence of TAMs) in the tumor microenvironment. These studies would be the first to describe an immune related function for HUNK where tumor cell intrinsic signaling driven by HUNK regulates paracrine signaling to TAMs.