ArticleProceedings of the National Academy of Sciences of the United States of America2014
Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers.
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Who cites it
114 citing papers in PubMed, 174 citations in OpenAlex.
- Vitamin e-loaded membrane dialyzers reduce hemodialysis inflammaging.BMC nephrology · 2019Trial
- Nitric oxide-driven Warburg reprogramming at the NOS2-COX2 axis: An integrative engine of cancer hallmarks.Redox biology · 2026Review
- NOS2 and COX2 impact the spatial landscape of CD8Redox biology · 2026Review
- NCancer reports (Hoboken, N.J.) · 2026Article
- Article
- Gasotransmitters bridging tumor biology and immunity: from pathophysiological insights to therapeutic potential.Frontiers in immunology · 2026Review
- Elevated tumor NOS2/COX2 promotes immunosuppressive phenotypes associated with poor survival in ER- breast cancer.JCI insight · 2025Article
- Article
- Real-time nitric oxide detection in cytokine stimulated cancer cells and macrophages.Nitric oxide : biology and chemistry · 2025Article
- Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome.Nature communications · 2025Article
- Neuropilin-2-expressing breast cancer cells mitigate radiation-induced oxidative stress through nitric oxide signaling.The Journal of clinical investigation · 2024Article
- Tumor NOS2 and COX2 Spatial Juxtaposition with CD8+ T Cells Promote Metastatic and Cancer Stem Cell Niches that Lead to Poor Outcome in ER- Breast Cancer.Cancer research communications · 2024Article
- Xanthene-Based Dyes for Photoacoustic Imaging and their Use as Analyte-Responsive Probes.Chemistry (Weinheim an der Bergstrasse, Germany) · 2024Article
- Hydrogen Therapy Reverses Cancer-Associated Fibroblasts Phenotypes and Remodels Stromal Microenvironment to Stimulate Systematic Anti-Tumor Immunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer.International journal of molecular sciences · 2024Review
- Article
- Upregulation of iNOS/NO in Cancer Cells That Survive a Photodynamic Challenge: Role of No in Accelerated Cell Migration and Invasion.International journal of molecular sciences · 2024Review
- Adjuvant COX inhibition augments STING signaling and cytolytic T cell infiltration in irradiated 4T1 tumors.JCI insight · 2024Article
- Deconvoluting nitric oxide-protein interactions with spatially resolved multiplex imaging.Chemical science · 2024Article
- Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome.Research square · 2024Article
54 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
Inflammation is widely recognized as an inducer of cancer progression. The inflammation-associated enzyme, inducible nitric oxide synthase (NOS2), has emerged as a candidate oncogene in estrogen receptor (ER)-negative breast cancer, and its increased expression is associated with disease aggressiveness and poor survival. Although these observations implicate NOS2 as an attractive therapeutic target, the mechanisms of both NOS2 induction in tumors and nitric oxide (NO)-driven cancer progression are not fully understood. To enhance our mechanistic understanding of NOS2 induction in tumors and its role in tumor biology, we used stimulants of NOS2 expression in ER(-) and ER(+) breast cancer cells and examined downstream NO-dependent effects. Herein, we show that up-regulation of NOS2 occurs in response to hypoxia, serum withdrawal, IFN-γ, and exogenous NO, consistent with a feed-forward regulation of NO production by the tumor microenvironment in breast cancer biology. Moreover, we found that key indicators of an aggressive cancer phenotype including increased S100 calcium binding protein A8, IL-6, IL-8, and tissue inhibitor matrix metalloproteinase-1 are up-regulated by these NOS2 stimulants, whereas inhibition of NOS2 in MDA-MB-231 breast cancer cells suppressed these markers. Moreover, NO altered cellular migration and chemoresistance of MDA-MB-231 cells to Taxol. Most notably, MDA-MB-231 tumor xenographs and cell metastases from the fat pad to the brain were significantly suppressed by NOS2 inhibition in nude mice. In summary, these results link elevated NOS2 to signals from the tumor microenvironment that arise with cancer progression and show that NO production regulates chemoresistance and metastasis of breast cancer cells.
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