S-Nitrosylation of EGFR and Src Activates an Oncogenic Signaling Network in Human Basal-Like Breast Cancer

Abstract

Increased inducible nitric oxide synthase (NOS2) expression in breast tumors is associated with decreased survival of estrogen receptor-negative (ER−) breast cancer patients. We recently communicated the preliminary observation that nitric oxide (NO) signaling results in EGFR tyrosine phosphorylation. To further define the role of NO in the pathogenesis of ER− breast cancer, we examined the mechanism of NO-induced EGFR activation in human ER− breast cancer. NO was found to activate EGFR and Src by a mechanism that includes S-nitrosylation. NO, at physiologically relevant concentrations, induced an EGFR/Src-mediated activation of oncogenic signal transduction pathways (including c-Myc, Akt and β-catenin) and the loss of PP2A tumor suppressor activity. Additionally, NO signaling increased cellular EMT, expression and activity of COX-2 and chemoresistance to adriamycin and paclitaxel. When connected into a network, these concerted events link NO to the development of a stem cell-like phenotype, resulting in the upregulation of CD44 and STAT3 phosphorylation. Our observations are also consistent with the finding that NOS2 is associated with a basal-like transcription pattern in human breast tumors. These results indicate that the inhibition of NOS2 activity or NO signaling networks may have beneficial effects in treating basal-like breast cancer patients.

Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression

“…In tumors, nutrient deprivation results from limited vascularization and forces tumor adaptation via activation of angiogenic, invasion, and survival pathways (12). NO augments tumor cell survival, implicating NOS2 as a mediator of tumor survival under these conditions (4,20,34,35). Importantly, the current study shows positive feed-forward regulation of NOS2 protein and mRNA expression by exogenous NO under SW conditions, because AG suppressed NOS2 levels, which then rebounded in the presence of exogenous NO donor.…”

Itinéraire d’un agent double

“…Cela permet donc d'envisager les donneurs de NO comme de nouveaux espoirs thérapeutiques. De nombreuses classes de donneurs de NO existent (Tableau II) et les progrès dans leur synthèse ont permis de développer de nouvelles molécules qui sont mieux tolérées par l'organisme, comme les dérivés du NO-aspirine, qui 3 La doxorubicine (Adriamycine™) se fixe sur les structures nucléaires de la cellule, bloquant la synthèse de l'ADN et de l'ARN : c'est un intercalant de l'ADN. …”

“…À noter que plusieurs composants de ces voies de signalisation sont régulés par le NO ( Figure 2). [3]. Bien que l'ensemble de ces résultats apparaissent contradictoires, les sites exacts de la S-nitrosylation qui sont associés à l'activation de l'EGFR restent encore à déterminer.…”

Nitric oxide: Protein tyrosine phosphorylation and protein S-nitrosylation in cancer

“…[28][29][30][31] The major focus of this review is on the role of protein S-nitrosylation and its interactions with protein phosphorylation in oncogenic and anti-oncogenic signaling pathways. Discussion of oncogenic signaling associated with the other modes of NO signaling can be found elsewhere.…”

“…[28] Tyrosine phosphorylation and S-nitrosylation of b-catenin is related to tumor progression. Activation of Src in endothelial cells phosphorylated b-catenin on Tyr654, while eNOS-derived NO nitrosylated b-catenin on Cys619, leading to dissociation of b-catenin from its partner VE-cadherin in adheren junctions.…”