Abstract P2-05-15: NOS2&COX2 activation of TLR4 & EGFR signalling causes poor outcome in oestrogen receptor-negative breast cancer via pro-survival signals and immune polarisation

Abstract

Abstract Background We seek to further elucidate mechanisms by which inflammatory mediators promote estrogen receptor (ER)-negative breast cancer progression and poor survival. We previously reported association between inducible nitric oxide synthase (NOS2) and poor outcome in ER-negative tumours. In tumours aberrant NOS2 induction facilitates tissue remodelling and stimulates neovascularisation. Also involved in inflammation and wound healing is cyclooxygenase-2 (COX2). We demonstrated that COX2 is associated with Akt activation and poor outcome in ER-negative tumours. We hypothesise that co-expression COX2 with NOS2 in ER-negative tumours amplifies effects of NOS2 on poor outcome, via EGFR and TLR4 signalling loop activation, and polarization of the tumour immune-compartment to pro-tumorigenic M2 phenotype. Methodology We determined the association of NOS2 and COX2 co-expression on breast cancer specific survival in ER-negative and triple negative breast tumours (N=102), via immunohistochemistry and cox regression statistical analysis. To explore the mechanism of NOS2 induction of COX2 through transactivation of EGFR, NO donors in combination with EGFR inhibitors were used to determine if NO exposure results in amplified EGFR and PGE2 pro-survival and pro-metastatic signalling in triple negative breast cancer cell lines. Finally, we explored the ability of NO to modify the ability of triple negative breast cancer secretome to induce polarisation of macrophages to a pro-tumorigenic M2 phenotype. Results Co-expression of NOS2 and COX2 in triple negative breast cancer results in poor outcome, via activation of pro-survival signalling and modification of the immune compartment to a pro-tumorigenic M2 associated phenotype. NO induces activation of growth factor signalling pathways and secretion of M2 promoting cytokines that induce THP1 macrophage polarization to an M2 phenotype. Citation Format: Glynn S, Garrrido-Cuesta P, Wink D, Ridnour L, Ambs S, Keane M, Walsh E, Callagy G. NOS2&COX2 activation of TLR4 & EGFR signalling causes poor outcome in oestrogen receptor-negative breast cancer via pro-survival signals and immune polarisation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-15.