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

Abstract

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.

A comprehensive overview of metaplastic breast cancer: clinical features and molecular aberrations

“…TNBC expresses higher levels of nitric oxide (NO), which is estimated by nitrate levels, than HER2+ or luminal breast cancers [ 47 ]. Furthermore, previous in vitro studies have shown that TNBC tumors expressing inducible nitric oxide synthase (iNOS) produce moderate to high levels of NO, and the increased iNOS activity may confer resistance to chemotherapy [ 48 ]. A preclinical study demonstrated that combining docetaxel with pan-NOS inhibitor NG-monomethyl- l -arginine acetate (L-NMMA) in a xenograft model of MDA-MB-231 decreased Ki67 proliferating cells, enhanced tumor apoptosis, and reduced tumor-initiating capacity of residual tumor cells after chemotherapy to a larger degree than docetaxel alone [ 29 ].…”

Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

“…We assessed whether IS can modulate cancer hallmarks that were modulated by other cytostatic bacterial metabolites [ 16 , 17 , 41 , 47 , 61 , 62 , 63 , 64 , 65 ]. First, we assessed oxidative/nitrosative stress markers, as these are major regulators of cancer hallmarks and cancer progression [ 66 , 67 , 68 , 69 , 70 ]. Levels of thiobarbituric acid-reactive substances (TBARS) and 4-hydroxynonenal (4HNE), both markers of lipid oxidative damage, increased when cells were treated with IS ( Figure 3 A,B).…”

An in Vitro Study in Which New Boron Derivatives Maybe an Option for Breast Cancer Treatment

“…Principal et al [28] suggested that higher levels of iNOS may serve as a marker of poor prognosis and aggressiveness in patients with breast cancer. Wash et al [29] showed that iNOS has been shown to induce p53 mutation accumulation and activation of the epidermal growth factor receptor; all of which are key components of breast cancer biology. Moreover, iNOS predicts poor outcome in breast cancer, and iNOS inhibitors show efficacy when used in combination with chemotherapy.…”