Nitric oxide dependent metabolic and genetic dysregulation in metastatic triple-negative breast cancer.

Authors

Jennifer N Daw, Pricila K Moly, Su Chung, Sarah Young, Nhi Van, Sara Centuori, David G Besselsen, Nathan Ellis, Ronald L Heimark, William R Montfort

Published in

The Journal of biological chemistry. Pages 113526. Sep 08, 2026. Epub Sep 08, 2026.

Abstract

Chronic inflammation drives many diseases, including cancer, where inflammation is associated with metastasis, the cause of death in 90% of cancer fatalities. Tumor inflammation drives inducible nitric oxide synthase (NOS2) and cyclooxygenase 2 (COX2) expression, each of which is associated with poor outcomes in cancer. Here, we knocked out the NOS2 gene in the murine triple-negative breast cancer allograft tumor model 4T1 and examined metastatic spread from primary mammary tumors to lung in BALB/c mice with intact immune systems. Remarkably, while the parental 4T1 tumors were highly metastatic, metastasis from 4T1 NOS2^-/- tumors was nearly eliminated. In cell culture, we find that nitric oxide (NO) from NOS2 induces a glycolytic phenotype, epitrascriptomic dysregulation, and prostaglandin E₂ synthesis by stimulating COX2. Cytokine addition led to DNA damage, presumably from NO. Human colorectal cancer cell line DLD1 yielded similar results. RNA sequencing of 4T1 cells revealed a NOS2-dependent reduction in mRNAs associated with regulation of chromosome and DNA replication, including cell cycle checkpoints, as well as mRNAs associated with RNA demethylation, including tRNA demethylation. Immunoprofiling of the tumor microenvironment revealed immunosuppressed primary tumors that were low in cytotoxic T cells and high in myeloid derived suppressor cells expressing interferon gamma, which induces NOS2 expression. Taken together, these data suggest high NOS2 in tumor cells may drive metastasis through a broad accumulation of cancer-associated factors - including metabolic dysregulation, genetic dysregulation, and an increase in inflammatory prostaglandins - all of which contribute to aggressive cancers.

PMID:
42710678
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.

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