Publication

Impact of inducible nitric oxide synthase (inos) expression on triple negative breast cancer outcome and activation of egfr and erk signaling pathways

Garrido, Pablo
; 
Shalaby, Aliaa
; 
Walsh, Elaine M.
; 
Keane, Nessa
; 
Webber, Mark
; 
Keane, Maccon
; 
Sullivan, Francis J
; 
Kerin, Michael J.
; 
Callagy, Grace
; 
Ryan, Aideen E.
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Repository DOI
Publication Date
2017-07-26
Keywords
triple negative breast cancer, egfr, inflammation, metastasis, nitric oxide, nf-kappa-b, randomized phase-ii, prostate-cancer, cells, inflammation, inhibitors, growth, survival, progression, metastasis
Type
Article
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Citation
Garrido, Pablo; Shalaby, Aliaa; Walsh, Elaine M. Keane, Nessa; Webber, Mark; Keane, Maccon; Sullivan, Francis J; Kerin, Michael J.; Callagy, Grace; Ryan, Aideen E.; Glynn, Sharon A. (2017). Impact of inducible nitric oxide synthase (inos) expression on triple negative breast cancer outcome and activation of egfr and erk signaling pathways. Oncotarget 8 (46), 80568-80588
Abstract
Inflammation is implicated in triple negative breast cancer (TNBC) progression. TNBC carries a worse prognosis than other breast cancer subtypes, and with the clinical and molecular heterogeneity of TNBC, there is a lack of effective therapeutic targets available. Identification of molecular targets for TNBC subtypes is crucial towards personalized patient stratification. Inducible nitric oxide synthase (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. Herein we report that iNOS is associated with disease recurrence, distant metastasis and decreased breast cancer specific survival in 209 cases of TNBC. Employing TNBC cell lines representing normal basal breast, and basal-like 1 and basal-like 2 tumors, we demonstrate that nitric oxide (NO) induces EGFR-dependent ERK phosphorylation in basal-like TNBC cell lines. Moreover NO mediated cell migration and cell invasion was found to be dependent on EGFR and ERK activation particularly in basal-like 2 TBNC cells. This occurred in conjunction with NF-.B activation and increased secretion of pro-inflammatory cytokines IL-8, IL-1 alpha and TNF-a. This provides substantial evidence for EGFR as a therapeutic target to be taken into consideration in the treatment of a specific subset of basal-like TNBC overexpressing iNOS.
Funder
Publisher
Impact Journals, LLC
Publisher DOI
10.18632/oncotarget.19631
Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland
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Externally hosted open access publications with University of Galway authors (2)