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dc.contributor.authorBasudhar, Debashree
dc.contributor.authorGlynn, Sharon A.
dc.contributor.authorGreer, Madison
dc.contributor.authorSomasundaram, Veena
dc.contributor.authorNo, Jae Hong
dc.contributor.authorScheiblin, David A.
dc.contributor.authorGarrido, Pablo
dc.contributor.authorHeinz, William F.
dc.contributor.authorRyan, Aideen E.
dc.contributor.authorWeiss, Jonathan M.
dc.contributor.authorCheng, Robert Y. S.
dc.contributor.authorRidnour, Lisa A.
dc.contributor.authorLockett, Stephen J.
dc.contributor.authorMcVicar, Daniel W.
dc.contributor.authorAmbs, Stefan
dc.contributor.authorWink, David A.
dc.date.accessioned2018-09-20T16:00:41Z
dc.date.available2018-09-20T16:00:41Z
dc.date.issued2017-10-27
dc.identifier.citationBasudhar, Debashree; Glynn, Sharon A. Greer, Madison; Somasundaram, Veena; No, Jae Hong; Scheiblin, David A.; Garrido, Pablo; Heinz, William F.; Ryan, Aideen E.; Weiss, Jonathan M.; Cheng, Robert Y. S.; Ridnour, Lisa A.; Lockett, Stephen J.; McVicar, Daniel W.; Ambs, Stefan; Wink, David A. (2017). Coexpression of nos2 and cox2 accelerates tumor growth and reduces survival in estrogen receptor-negative breast cancer. Proceedings of the National Academy of Sciences 114 (49), 13030-13035
dc.identifier.issn0027-8424,1091-6490
dc.identifier.urihttp://hdl.handle.net/10379/10375
dc.description.abstractProinflammatory signaling pathways are commonly up-regulated in breast cancer. In estrogen receptor-negative (ER-) and triple-negative breast cancer (TNBC), nitric oxide synthase-2 (NOS2) and cyclooxygenase-2 (COX2) have been described as independent predictors of disease outcome. We further explore these findings by investigating the impact of their coexpression on breast cancer survival. Elevated coexpression of NOS2/COX2 proteins is a strong predictor of poor survival among ER-patients (hazard ratio: 21). Furthermore, we found that the key products of NOS2 and COX2, NO and prostaglandin E2 (PGE2), respectively, promote feed-forward NOS2/COX2 crosstalk in both MDA-MB-468 (basal-like) and MDA-MB-231 (mesenchymal-like) TNBC cell lines in which NO induced COX2 and PGE2 induced NOS2 proteins. COX2 induction by NO involved TRAF2 activation that occurred in a TNF alpha-dependent manner in MDA-MB-468 cells. In contrast, NO-mediated TRAF2 activation in the more aggressive MDA-MB-231 cells was TNF alpha independent but involved the endoplasmic reticulum stress response. Inhibition of NOS2 and COX2 using amino-guanidine and aspirin/indomethacin yielded an additive reduction in the growth of MDAMB-231 tumor xenografts. These findings support a role of NOS2/COX2 crosstalk during disease progression of aggressive cancer phenotypes and offer insight into therapeutic applications for better survival of patients with ER-and TNBC disease.
dc.publisherProceedings of the National Academy of Sciences
dc.relation.ispartofProceedings of the National Academy of Sciences
dc.subjectbreast cancer
dc.subjectnitric oxide
dc.subjectpge2
dc.subjectnos2
dc.subjectcox2
dc.subjectcyclooxygenase-2 expression
dc.subjectbasal-like
dc.subjectinflammation
dc.subjectangiogenesis
dc.subjectcarcinoma
dc.subjecttumorigenesis
dc.subjectprogression
dc.subjectmetastasis
dc.subjectpathways
dc.titleCoexpression of nos2 and cox2 accelerates tumor growth and reduces survival in estrogen receptor-negative breast cancer
dc.typeArticle
dc.identifier.doi10.1073/pnas.1709119114
dc.local.publishedsourcehttp://www.pnas.org/content/114/49/13030.full.pdf
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