These data suggest that invasive breast carcinoma patients whose tumors express high COX-2 or have high infiltration of protumoral macrophages (CD163+) might benefit from a selective COX-2 inhibitor therapy, such as celecoxib. tumor microarray cohort included females, aged 18 to 80 years, with a median follow-up of 8.4 years. High expression of COX-2 (TN), CD68 (TS), and CD163 (TN and TS) predicted worse patient overall survival (OS). This notion was strengthened by the finding from the multivariate analysis that high numbers of CD163+ macrophages in the TS is an impartial prognostic factor. Overall collagen deposition was associated with high stromal expression LGALS13 antibody of COX-2 and CD163; however, total collagen deposition was not a predictor for OS. Conversely, local collagen density, alignment and perpendicular alignment to the tumor boundary (tumor-associated collagen signature-3) were predictors of OS. These results suggest that in invasive carcinoma, the localization of inflammatory cells and aligned collagen orientation predict poor patient survival. Additional clinical studies may help validate whether therapy with selective COX-2 inhibitors alters expression of CD68 and CD163 inflammatory markers. Yearly, more than 1.7 million women are diagnosed as having breast cancer worldwide. Despite the improvement in early detection and treatment, 31% of women diagnosed as having breast malignancy will succumb to this disease.1 Tumor-associated macrophages (TAMs) play a dynamic and multifaceted role in breast malignancy development. They produce different outcomes, depending on their protumor or?antitumor behavior. TAMs have served a dual role in?breast malignancy. They can produce an antitumorigenic effect?by activation of ILs and interferon, while also promoting a tumorigenic environment by GSK1265744 (GSK744) Sodium salt secreting diverse cytokines, growth factors, and proteases.2 Protumoral TAMs aid in?the?processes of angiogenesis, proliferation, immunosuppression, degradation of the extracellular matrix (ECM), promotion of breast tumor epithelial cell migration, and metastasis.3, 4 CD68 and CD163 are glycoproteins that are expressed in human monocytes and tissue macrophages.5, 6 CD163 is a scavenger receptor that is overexpressed by macrophages in an anti-inflammatory environment,7 and it is considered a highly specific monocyte/macrophage marker for polarized protumoral macrophages.6, 8, 9 On the other hand, CD68 is a pan-macrophage marker that recognizes both protumoral and antitumoral macrophages.5 There is evidence of macrophages in the tumor microenvironment expressing high cyclooxygenase 2 (COX-2) levels, and prostaglandin E2 (PGE2) production downstream of COX-2 is one of the key molecules that facilitates the protumoral capabilities of TAMs.10, 11 Through COX-2 enzymatic production of PGE2, macrophages can be stimulated to produce cytokines and growth factors that will promote more proinflammatory cell recruitment and the development of colitis-associated tumorigenesis.11 Chemoprevention by celecoxib in mammary carcinoma was first demonstrated in a 7,12-dimethylbenz(a)anthracene rat model, with significant reduction in incidence, number, and size of tumors.12 Elevated expression levels of COX-2 and PGE2 are key elements in the inflammatory response of mouse mammary tumors that arise in collagen-dense tissue, which leads to increased recruitment of TAMs, elevated levels of several cytokines, and enhanced proliferation; they ultimately promote tumor development.13 Consequently, it was found that COX-2 inhibition with celecoxib caused the decrease in the presence of TAMs in conjunction with diminished cytokine levels, smaller and less proliferative tumors specifically in the collagen-dense tumors. In addition, COX-2 inhibition decreased the amount of collagen in the stroma, suggesting that COX-2, through GSK1265744 (GSK744) Sodium salt enzymatic production of PGE2, has an important role in collagen deposition and macrophage recruitment to the tumor microenvironment and is essential in GSK1265744 (GSK744) Sodium salt the growth and spread of mammary tumors.13 There is evidence that this immune response and ECM play a critical role toward the development and progression of breast malignancy. There are several reports demonstrating that expression levels of COX-2 are elevated in breast, colorectal, and GSK1265744 (GSK744) Sodium salt other carcinomas in comparison to normal tissue.14, 15 Unlike COX-1, which is a constitutively expressed enzyme,16 COX-2 is an inducible enzyme that is activated at sites of injury as part of the GSK1265744 (GSK744) Sodium salt inflammatory response.17 Cyclooxygenases.