Hypothesis for the protumorigenic role of UA in the breast cancer microenvironment. UA is postulated to enter tumor associated and/or distant adipocytes through a UA-specific transporter (likely URAT1) where it activates the NADPH Oxidase (NOX), generating ROS. As observed in other inflammatory environments, UA at both normo- and hyperuricemic levels may simultaneously increase steady state mRNA expression of the leukocyte chemokine MCP-1 and decrease expression of the anti-inflammatory protein adiponectin. In addition, UA entering adipocytes may down-regulate expression of XOR which is known as a crucial upstream regulator of PPAR-γ, a master regulator of adipogenesis and adiponectin expression. Furthermore, as previously shown, UA may reduce levels of the macrophage antiinflammatory markers Arginase-1, CD36, and CD206, an effect transduced in part by inhibition of PPARγ sumoylation that in turn promotes macrophage inflammatory activation. Presently, the identity of the UA transporter mediating macrophage response to UA has not been identified. As an endogenous product of leukocytes, XOR activity may exert many effects on inflammatory potential, cytokine synthesis, and lipid uptake. Together, these findings support the hypothesis that hyperuricemia might be partially responsible for the low grade inflammation present in the breast tumor microenvironment that contributes to tumor cell proliferation and metastasis.