title: S-nitrosylation of EGFR and Src activates an oncogenic signaling network in human basal-like breast cancer.
abstract: Increased inducible nitric oxide synthase (NOS2) expression in breast tumors is associated with decreased survival of estrogen receptor negative (ER-) breast cancer patients. We recently communicated the preliminary observation that nitric oxide (NO) signaling results in epidermal growth factor receptor (EGFR) tyrosine phosphorylation. To further define the role of NO in the pathogenesis of ER- breast cancer, we examined the mechanism of NO-induced EGFR activation in human ER- breast cancer. NO was found to activate EGFR and Src by a mechanism that includes S-nitrosylation. NO, at physiologically relevant concentrations, induced an EGFR/Src-mediated activation of oncogenic signal transduction pathways (including c-Myc, Akt, and β-catenin) and the loss of PP2A tumor suppressor activity. In addition, NO signaling increased cellular EMT, expression and activity of COX-2, and chemoresistance to adriamycin and paclitaxel. When connected into a network, these concerted events link NO to the development of a stem cell-like phenotype, resulting in the upregulation of CD44 and STAT3 phosphorylation. Our observations are also consistent with the finding that NOS2 is associated with a basal-like transcription pattern in human breast tumors. These results indicate that the inhibition of NOS2 activity or NO signaling networks may have beneficial effects in treating basal-like breast cancer patients.
authors.affiliation: Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Switzer
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Glynn
authors.forename: Robert Y-S
authors.initials: RY
authors.lastname: Cheng
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Green
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism; D002280:Basal Cell Carcinoma / Q000201:enzymology* / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000166:cytology; D051379:Mice; D009566:Nitrates / Q000032:analysis / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D009573:Nitrites / Q000032:analysis / Q000378:metabolism; D015538:Nitrosation; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C489427:MYC protein, human; D009566:Nitrates; D009573:Nitrites; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2