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

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

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158 Scopus citations


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.

Original languageEnglish
Article number25
JournalBreast Cancer Research
Issue number1
StatePublished - Feb 22 2015

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health/National Cancer Institute grant R01 CA138197 (JCC), U54 CA149196 (JCC), Golfers Against Cancer (JCC), Breast Cancer Research Foundation (JCC), Causes for a Cure (JCC), Team Tiara (JCC), Emily W. Herrman Cancer Research Laboratory (JCC), Department of Defense Innovator Expansion Award BC104158 (JCC), Komen for Cure KG 081694 (JCC), National Institutes of Health Merit Award grant R37 HL87062 (SSG), and Fundacion Alfonso Martin Escudero (SG-P). We thank Dr. Madhumita Ghosh for critical reading and editing of the manuscript.

Publisher Copyright:
© Granados-Principal et al.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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