Abstract 3789: Role of NOS2-COX2 crosstalk in tumor microenvironment of estrogen receptor-negative breast cancer and its therapeutic implications

Tumor is often described as a wound that never heals. This leads to a chronic inflammatory tumor microenvironment characterized by infiltration of M2 macrophages and Th2 cells causing dysregulated release of multiple cytokines, chemokines and growth factors, thus creating a conducive environment for tumor growth and metastasis. In spite of significant progress in breast cancer treatment, metastatic breast cancer still remains a major health hazard with a high mortality rate among women. Moreover, there is cellular heterogeneity within and among different breast tumors, which poses a significant challenge in developing effective therapeutics, thus making it important to understand subtype-specific mechanisms. Our laboratory and other groups have previously shown that inducible nitric oxide synthase (NOS2), an enzyme involved in production and regulation of endogenous nitric oxide (NO), is a predictor of poor survival among highly metastatic ER-negative (ER-) breast cancer patients. Another proinflammatory enzyme, cyclooxygenase-2 (COX2,) responsible for conversion of arachidonic acid to prostaglandin E2 (PGE2), is also highly expressed in breast cancer and is detectable in ductal carcinoma in situ, invasive breast carcinoma, and metastatic lesions. We investigated the role of inflammation associated enzymes, NOS2 and COX2, and established that their simultaneous elevated expression significantly reduced patient survival (33%) when compared to greater than 95% survival of ER- patients with low NOS2/COX2 tumor expression. We further investigated their tumor subtype specific novel signaling mechanism in vitro and showed TNFα and/or endoplasmic reticulum stress as key players. Proinflammatory cytokines present in tumor microenvironment play a key role in regulation of this pathway and effectiveness of chemotherapeutics. Moreover, the ability of NOS2 and COX2 to regulate different cytokines in the tumor microenvironment further emphasizes the importance of their crosstalk in tumor progression, metastasis and ability of cancer cells to escape immune surveillance. Last, we demonstrated that simultaneous inhibition of COX2 and NOS2 using commercially available inhibitors significantly reduced tumor growth in murine models of ER- breast cancer, thus suggesting the beneficial effects of dual NOS2/COX2 therapy. Citation Format: Debashree Basudhar, Sharon Glynn, Madison Greer, Veena Somasundaram, Jae H. No, David A. Scheiblin, Pablo Garrido, William F. Heinz, Aideen E. Ryan, Jonathan M. Weiss, Robert Y. Cheng, Lisa A. Ridnour, Stephen J. Lockett, Daniel W. McVicar, Stefan Ambs, David A. Wink. Role of NOS2-COX2 crosstalk in tumor microenvironment of estrogen receptor-negative breast cancer and its therapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3789.