Coexpression of nos2 and cox2 accelerates tumor growth and reduces survival in estrogen receptor-negative breast cancer
Basudhar, 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.
Basudhar, 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.
Publication Date
2017-10-27
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Article
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Basudhar, 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
Abstract
Proinflammatory 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.
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Proceedings of the National Academy of Sciences
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Attribution-NonCommercial-NoDerivs 3.0 Ireland