Breast cancer is the most common type of cancer in American women, excluding skin cancers, with 200,000 diagnosed cases and causing 40,000 deaths yearly. There are many risks that are concomitant with breast cancer, and increased breast density is associated with 4-6 times higher risk of breast cancer. Collagen I is the most abundant protein in breast stroma and it has been correlated to elevated breast density. In addition, in a rodent model of breast cancer, high levels of collagen present in the tumor microenvironment leads to a more aggressive mammary tumor formation and progression to metastasis. Furthermore, in vitro experiments show that elevated collagen density increases expression of PTGS2 (prostaglandin-endoperoxide synthase 2), the gene for cyclooxygenase-2 (COX-2), which is an enzyme involved in the inflammation process. This thesis investigates the role of COX-2 and its impact in tumor progression within a collagen-dense microenvironment. A collagen-dense (HD) mammary cancer mouse model was utilized in two different ways: therapeutically and preventively. In the therapeutic model, tumors in the HD animals were larger, more proliferative, expressed higher levels of COX-2, had more inflammatory cells and higher levels of cytokines than tumors in the wild-type (wt) mice. Conversely, after treatment with the COX-2 inhibitor, celecoxib, all these effects were reversed. Next, when celecoxib was used as a preventive agent, tumors in HD animals were fewer and smaller than untreated HD animals. Furthermore, the associations between COX-2 overexpression, collagen deposition and high infiltration of tumor-associated macrophages (TAMs) were examined utilizing a human invasive carcinoma tissue microarray containing 371 cases. COX-2 overexpression in the tumor-associated stroma (TS) was associated with increased collagen deposition. Additionally, localization of COX-2 and TAMs within the tumor microenvironment significantly affected patient outcome. For instance, COX-2 overexpression in the tumor nest (TN) was associated with worse patient outcome and CD68+, CD163+ TAMs and their co-expression with COX-2 in the TS led to poor patient prognosis. Findings of this work suggest that invasive carcinoma patients with collagen-dense tumors, overexpressing COX-2 and/ or have high infiltration of TAM’s will benefit from treatment with a COX-2 selective inhibitor, such as celecoxib.