Basal-like breast cancer is an aggressive disease with limited therapeutic options because these tumors frequently express the ‘triple-negative' phenotype. We have recently reported that inducible nitric oxide synthase (NOS2) is a strong predictor of survival in patients with estrogen receptor negative [ER(–)] breast cancer, and that NOS2 expression is correlated with a basal-like phenotype. Recent reports also describe the pro-tumor effects of NO in breast and many other types of cancer. NO promotes cancer progression by activating several oncogenic signaling pathways such as extracellular signal-regulated kinases (ERK)-1/2, phosphoinositide 3-kinases (PI3K)/Akt, and c-Myc. Protein phosphatase 2A (PP2A) is a tumor suppressor that negatively regulates the same cancer-related signaling pathways that are activated by NO. PP2A activity is suppressed in tumor cells, but potential pharmacological agents have recently been described to increase PP2A activity in ER(–) breast cancer cells. We examine here the various functions of NO and PP2A in breast cancer and propose a novel mechanism by which activation of PP2A antagonizes NO signaling that promotes ER(–) breast cancer.