The breast tumor microenvironment (TME) is a diverse area where complex interactions between the extracellular matrix (ECM) and multiple cell types (tumor epithelial, endothelial, and inflammatory cells, fibroblasts, and adipocytes) occur resulting in tumor promotion, invasion and metastasis. Differences in breast tissue density have been correlated with a 4-6-fold increased risk for developing breast cancer, and are associated with increased stromal deposition of the ECM protein, collagen I. In a transgenic mouse model of increased collagen (Col1A1Tm1Jae), there is a 3-fold increase in mouse mammary tumor virus – polyoma middle T antigen (MMTV-PyMT) tumor formation and lung metastases compared to control, wild type mice. Of the non-malignant cells in the TME, tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) have been shown to alter the TME and ECM, enhance tumor cell migration and invasion, stimulate angiogenesis, and suppress antitumor immunity. The direct interaction of both increased collagen and myeloid cell recruitment leading to increased cancer progression and metastasis has not been characterized. We hypothesized that a collagen-dense TME recruits a population of myeloid cells, which promote tumor progression and metastasis. We show that the collagen-dense TME cytokine cross talk supports neutrophil and monocyte recruitment, as suggested by expression of the cytokine GM-CSF in vivo. Depleting neutrophils with anti-Ly6G (1A8) reduces the number of tumors and tumor burden in collagen-dense mice compared to anti-IgG control mice. These effects are not seen in treated wild type mice compared to control mice. Of importance, neutrophil depletion reduces metastasis in over 80% of treated collagen-dense mice compared to control mice. In contrast, wild type mice show an increase in metastasis with anti-Ly6G treatment. The in vitro data presented here focuses on macrophages and demonstrates that macrophage cell lines respond to collagen-dense microenvironments by evading apoptotic signals and increasing proliferation signals. Our study supports the idea that the collagen-dense TME can manipulate other cells in the TME specifically, the pro and anti-tumor functions of Ly6G+ neutrophils in mammary carcinoma. This work is supported by NIH grants (NIH-CA-114462 and NIH-U54-CA163131) to P.J.K. and NSF Graduate Research Fellowship (2011129283) to M.G.G.M.