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Breast Cancer Research
Published in: Breast Cancer Research 1/2015

Open Access 01-12-2015 | Research article

Inhibition of iNOS as a novel effective targeted therapy against triple-negative breast cancer

Authors: Sergio Granados-Principal, Yi Liu, Maria L Guevara, Elvin Blanco, Dong Soon Choi, Wei Qian, Tejal Patel, Angel A Rodriguez, Joseph Cusimano, Heidi L Weiss, Hong Zhao, Melissa D Landis, Bhuvanesh Dave, Steven S Gross, Jenny C Chang

Published in: Breast Cancer Research | Issue 1/2015

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Abstract

Introduction

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with no effective targeted therapy. Inducible nitric oxide synthase (iNOS) is associated with poor survival in patients with breast cancer by increasing tumor aggressiveness. This work aimed to investigate the potential of iNOS inhibitors as a targeted therapy for TNBC. We hypothesized that inhibition of endogenous iNOS would decrease TNBC aggressiveness by reducing tumor initiation and metastasis through modulation of epithelial-mesenchymal transition (EMT)-inducing factors.

Methods

iNOS protein levels were determined in 83 human TNBC tissues and correlated with clinical outcome. Proliferation, mammosphere-forming efficiency, migration, and EMT transcription factors were assessed in vitro after iNOS inhibition. Endogenous iNOS targeting was evaluated as a potential therapy in TNBC mouse models.

Results

High endogenous iNOS expression was associated with worse prognosis in patients with TNBC by gene expression as well as immunohistochemical analysis. Selective iNOS (1400 W) and pan-NOS (L-NMMA and L-NAME) inhibitors diminished cell proliferation, cancer stem cell self-renewal, and cell migration in vitro, together with inhibition of EMT transcription factors (Snail, Slug, Twist1, and Zeb1). Impairment of hypoxia-inducible factor 1α, endoplasmic reticulum stress (IRE1α/XBP1), and the crosstalk between activating transcription factor 3/activating transcription factor 4 and transforming growth factor β was observed. iNOS inhibition significantly reduced tumor growth, the number of lung metastases, tumor initiation, and self-renewal.

Conclusions

Considering the effectiveness of L-NMMA in decreasing tumor growth and enhancing survival rate in TNBC, we propose a targeted therapeutic clinical trial by re-purposing the pan-NOS inhibitor L-NMMA, which has been extensively investigated for cardiogenic shock as an anti-cancer therapeutic.
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Metadata
Title
Inhibition of iNOS as a novel effective targeted therapy against triple-negative breast cancer
Authors
Sergio Granados-Principal
Yi Liu
Maria L Guevara
Elvin Blanco
Dong Soon Choi
Wei Qian
Tejal Patel
Angel A Rodriguez
Joseph Cusimano
Heidi L Weiss
Hong Zhao
Melissa D Landis
Bhuvanesh Dave
Steven S Gross
Jenny C Chang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2015
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-015-0527-x

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