Review of Triple Negative Breast Cancer and the Impact of Inducible Nitric Oxide Synthase on Tumor Biology and Patient Outcomes.

Triple negative breast cancers (TNBCs), which are defined as estrogen-receptor, progesterone-receptor, and HER2-receptor negative, account for 10-20% of breast cancers, and they are associated with early metastasis, chemotherapeutic resistance, and poor survival rates. One aspect of TNBC that complicates its prognosis and the development of new molecular therapeutic targets is its clinical and molecular heterogeneity. Herein we compare TNBC and basal cytokeratin-positive breast cancers. We examine the different TNBC molecular subtypes, based on gene expression profiling, which include basal-like, mesenchymal, and luminal androgen receptors, in the context of their biology and impact on TNBC prognosis. We explore the potential role of inducible nitric oxide synthase (iNOS) in TNBC tumor biology and treatment responses. iNOS has been shown to induce p53 mutation accumulation, basal-like gene signature enrichment, and transactivation of the epidermal growth factor receptor (EGFR) via S-nitrosylation, all of which are key components of TNBC biology. Moreover, iNOS predicts poor outcome in TNBC, and iNOS inhibitors show efficacy against TNBC when used in combination with chemotherapy. We discuss molecular targeted approaches, including EGFR, PARP, and VEGF inhibitors and immunotherapeutics, that are under consideration for the treatment of TNBC and what role, if any, iNOS may play in their success.