title: Inhibition of iNOS as a novel effective targeted therapy against triple-negative breast cancer.
abstract: BACKGROUND
  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.
authors: Sergio
authors: S
authors: Granados-Principal
authors: Yi
authors: Y
authors: Liu
authors: Maria L
authors: ML
authors: Guevara
authors: Elvin
authors: E
authors: Blanco
authors: Dong Soon
authors: DS
authors: Choi
authors: Wei
authors: W
authors: Qian
authors: Tejal
authors: T
authors: Patel
authors: Angel A
authors: AA
authors: Rodriguez
authors: Joseph
authors: J
authors: Cusimano
authors: Heidi L
authors: HL
authors: Weiss
authors: Hong
authors: H
authors: Zhao
authors: Melissa D
authors: MD
authors: Landis
authors: Bhuvanesh
authors: B
authors: Dave
authors: Steven S
authors: SS
authors: Gross
authors: Jenny C
authors: JC
authors: Chang
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D016212:Transforming Growth Factor beta / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016212:Transforming Growth Factor beta; D052247:Nitric Oxide Synthase Type II