Over the past twenty years, studies have shown that epithelial cancers grow in a specific environment characterized by tumor-induced changes ofthe infiltrating immune cells. This symbiotic relationship is critical for tumor growth and more importantly for tumor metastasis. Clearly a better understanding of these processes and the tumor types associated with each is critical to enhancing our understanding and treatment of malignant disease. During that same time period, it has been clear that the traditional approach to evaluate breast cancer using tumor histology does not adequately reflect the diversity of biology and the heterogeneity of this disease. As a result, new approaches to classifying breast cancer have been generated. The most commonly used, pioneered by this SPORE program, utilizes the expression of an intrinsic set of genes generated using cDNA microarray technology. Four different intrinsic subtypes were described-luminal A, HER-2-enriched, basal-like and normal-breast like. Interestingly, these different subtypes were associated with different clinical outcomes. Most recently, the Perou laboratory has identified a fifth subtype that is enriched in genes associated with tumor initiating cells and epithelial to mesenchymal transition. Patients with this subtype termed claudin-low have the poorest survival compared to patients with the other intnnsic subtypes. Our group has found that the claudin-low subtype, medullary cancer and some basal-like tumors are heavily infiltrated with immune cells. Quite recently we have found that the immune Infiltrate is critical to the growth and metastasis of these tumors. The immune infiltration by T and B cells, macrophages, NK cells and myeloid-derived suppressor cells is due to the generation by these tumors and the surrounding stroma of proteins important in migration and invasion. The current project will focus on enhancing our understanding of how these immune cells potentiate local and metastatic tumor grov^h of claudin-low, medullary cancer and basal-like tumors. Additionally, we will use therapies that specifically target these immune cells in combination with conventional therapies as a novel approach to the treatment of these tumors.