Inflammation and Nitric Oxide Synthase 2 in driving poor prognosis in Era(-) Breast Cancer (#198)
Inflammation
generates reactive chemical species that induce conditions of oxidative
nitrosative stress as emerged as factor in poor outcome of many cancers. Our recent finding 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 through
nitrosation of key thiols and non heme metals at different specific
concentration stimulate pro-oncogenic mechanisms such as AKT, ERK, NFkB, AP-1,
and HIF-1a that lead to increase of metastatic and cancer
stem cells proteins as well as pro-angiogenic and immunosuppressive factors. In addition, we show that tumor suppressor
gene BRCA1 and PP2A are inhibited by these NO levels. In the induction of NOS2 was found to
dependent inflammatory mediators IFNg, IL6, PGE2, TNFa, and
TLR4 agonist (Heinecke et al, PNAS 2014).
Since NOS2 and NO also induce these factors, a critical feed-forward
autocrine loop is formed that drives poor outcome. These finding provide a novel model that
shows how NO can drive numerous inflammatory mechanism that leads to a more
aggressive landscape.