We have previously shown tumor suppressive effects of extracellular superoxide dismutase, EcSOD in breast cancer cells. In this study, an RTK signaling array revealed an inhibitory effect of EcSOD on c-Met phosphorylation and its downstream kinase c-Abl in MDA-MB231 cells. Moreover, an extracellular protein array showed that thrombospondin 1 (TSP-1), a scavenger of the c-Met ligand, hepatocyte growth factor (HGF) is significantly up-regulated in EcSOD overexpressing cells (Ec.20). We further determined the effects of EcSOD on HGF/c-Met-mediated cancer-fibroblast interactions by co-culturing normal fibroblasts (RMF) or RMF which overexpresses HGF (RMF-HGF) with MDA-MB231 cells. We observed that while RMF-HGF significantly promoted Matrigel growth of MDA-MB231, overexpression of EcSOD inhibited the HGF-stimulated growth. Similarly, a SOD mimetic, MnTE-2-PyP, inhibited HGF-induced growth and invasion of MDA-MB231. In addition, a long-term heterotypic co-culture study not only showed that Ec.20 cells are resistant to RMF-HGF-induced invasive stimulation but RMF-HGF that were co-cultured with Ec.20 cells showed an attenuated phenotype, suggesting an oxidative-mediated reciprocal interaction between the two cell types. In addition, we demonstrated that RMF-HGF showed an up-regulation of an ROS-generating enzyme, NADPH oxidase 4 (Nox4). Targeting this pro-oxidant significantly suppressed the activated phenotype of RMF-HGF in a collagen contraction assay, suggesting that RMF-HGF contributes to the oxidative tumor microenvironment. We have further shown that scavenging ROS with EcSOD significantly inhibited RMF-HGF-stimulated orthotopic tumor growth of MDA-MB231. This study suggests the loss of EcSOD in breast cancer plays a pivotal role in promoting the HGF/c-Met-mediated cancer-fibroblast interactions.