Chronic inflammation within the tumor microenvironment is a major driver of tumor progression and poor prognosis. Inducible nitric oxide synthase (NOS2) is present in numerous solid tumors. Estrogen receptor-negative (ER-) patients with high expression of tumor NOS2 have a poorer outcome than patients with low expression of NOS2. Furthermore, expression of NOS2 is associated with the basal-like breast cancer phenotype. Using an in vitro model, we have found that nitrosation of critical thiols and nitration of tyrosines lead to the activation of membrane receptors such as epithelial growth factor receptor, Src, Ras, and CD63. These nitric oxide-mediated events in itiate oncogenic signaling pathways such as PI3K/Akt, Ras/ERK, β-catenin, nuclear factor-κB, and AP-1. These data suggest that NOS2 can serve as a major "nonmutatational driver" of ER- breast cancer.