Inflammation generates reactive chemical species that induce conditions of oxidative or nitrosative stress and has emerged as a factor in poor outcome of many cancers. Our recent findings show that the inflammatory protein inducible nitric oxide synthase (iNOS) is a strong predictor of poor outcome in ER(-) patients (Glynn et al. JCI 2010), indicating that nitric oxide (NO) and related reactive nitrogen oxide species are involved in cancer progression. In vitro studies using ER(-) cell lines showed that fluxes of NO delivered by NO donors surprisingly mimic the relationship observed in the patient cohort. Using this model, we show that there is a concentration dependence on stimulation by NO of pro-oncogenic mechanisms such as AKT, ERK, NFkB, AP-1 and HIF-1a that lead to increase of metastatic and cancer stem cells proteins. Increased NO levels increasingly mediate nitrosation of critical thiols and tyrosine residues and in turn lead to development of more aggressive phenotypes. In this way NO donors can mimic induction of iNOS in cancer cells. These finding have provided a model of the tumor microenvironment that shows how NO and nitrosation can affect numerous mechanisms that lead to a more aggressive phenotype and a poor clinical outcome.

Oncogenic properties of nitrosation in ERa(-) breast cancer

245th National Meeting (2013)

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