The Oncogenic Properties Of The Redox Inflammatory Protein Inducible Nitric Oxide Synthase In ER(-) Breast Cancer

Abstract

Inflammation generates reactive chemical species that induce conditions of oxidative nitrosative stress as emerged as factor in poor outcome of many cancers. Our recent findings show that in the inflammatory protein inducible nitric oxide synthase (iNOS) is a strong predictor of poor outcome in ER(-) patients (Glynn et al. JCI 2010). Furthermore 46 genes, of which 23 were associated with basal like breast cancer, were elevated when iNOS high. In vitro studies using ER(-) cell lines showed that fluxes of nitric oxide (NO) delivered by NO donors surprising mimic this relationship in the patient cohort. Using this model, we show that NO at different specific concentrations stimulate pro-oncogenic mechanisms such as AKT, ERK, NFkB, AP-1, and HIF-1α that lead to increase of metastatic and cancer stem cells proteins. In addition, we show that tumor suppressor gene BRCA1 and PP2A are inhibited by these NO levels. Similarly other studies show that these concentrations of NO increase immunosuppressive proteins TGF-β and IL-10 in leukocytes to decrease efficacy of some anticancer therapies further contributing to pro-tumorigenic environment. Using this model we have identified several new compounds that have efficacy in xenographic models. These finding have provided a model that shows how NO can affect numerous mechanism that leads to a more aggressive phenotype.