title: Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression.
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.
authors.affiliation: Radiation Biology Branch, Tumor and Metastasis Biology Section, Pediatric Oncology Branch, and Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Heinecke
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: Robert Y S
authors.initials: RY
authors.lastname: Cheng
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Switzer
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lizardo
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Glynn
authors.forename: S Perwez
authors.initials: SP
authors.lastname: Hussain
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016895:Culture Media, Serum-Free; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D006146:Guanidines; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009569:Nitric Oxide / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D014408:Biomarkers, Tumor; D016895:Culture Media, Serum-Free; D006146:Guanidines; D009569:Nitric Oxide; D007371:Interferon-gamma; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine
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