title: Nitric Oxide Synthase-2-Derived Nitric Oxide Drives Multiple Pathways of Breast Cancer Progression.
abstract: Breast cancer is the second leading cause of cancer-related deaths among women in the United States. Development and progression of malignancy are associated with diverse cell signaling pathways that control cell proliferation, survival, motility, invasion, and metastasis. Recent Advances: An increasing number of clinical studies have implicated a strong relationship between elevated tumor nitric oxide synthase-2 (NOS2) expression and poor patient survival.
  
  
  
  Herein, we review what we believe to be key mechanisms in the role(s) of NOS2-derived nitric oxide (NO) as a driver of breast cancer disease progression. High NO increases cyclooxygenase-2 activity, hypoxia inducible factor-1 alpha protein stabilization, and activation of important cell signaling pathways, including phosphoinositide 3-kinase/protein kinase B, mitogen-activated protein kinase, epidermal growth factor receptor, and Ras, through post-translational protein modifications. Moreover, dysregulated NO flux within the tumor microenvironment has other important roles, including the promotion of angiogenesis and modulation of matrix metalloproteinase/tissue inhibitor matrix metalloproteinase associated with tumor progression.
  
  
  
  The elucidation of these and other NO-driven pathways implicates NOS2 as a key driver of breast cancer disease progression and provides a new perspective in the identification of novel targets that may be therapeutically beneficial in the treatment of estrogen receptor-negative disease. Antioxid. Redox Signal. 26, 1044-1058.
authors.affiliation: 1 Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, Maryland.
authors.forename: Debashree
authors.initials: D
authors.lastname: Basudhar
authors.affiliation: 1 Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, Maryland.
authors.forename: Veena
authors.initials: V
authors.lastname: Somasundaram
authors.affiliation: 1 Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, Maryland.
authors.forename: Graciele Almeida
authors.initials: GA
authors.lastname: de Oliveira
authors.affiliation: 2 Radiation Oncology Branch, National Cancer Institute , Bethesda, Maryland.
authors.forename: Aparna
authors.initials: A
authors.lastname: Kesarwala
authors.affiliation: 1 Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, Maryland.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Heinecke
authors.affiliation: 1 Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, Maryland.
authors.forename: Robert Y
authors.initials: RY
authors.lastname: Cheng
authors.affiliation: 3 Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland , Galway, Ireland .
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Glynn
authors.affiliation: 4 Laboratory of Human Carcinogenesis, National Cancer Institute , Bethesda, Maryland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
authors.affiliation: 1 Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, Maryland.
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.affiliation: 1 Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, Maryland.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D055550:Protein Stability; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
keywords: NOS2; biomarker; cancer progression; metastasis; nitric oxide