Abstract 3868: Aggressiveness niche within BRCA1-IRIS/TNBC tumors is supported by reciprocal interactions with the microenvironment
Authors: Abhilasha Sinha, Wael M. ElShamy
Journal: Cancer Research (2016)

Abstract Introduction: Bi-directional interactions with stromal cells promote metastasis from breast tumors. We aimed at determining the role these bi-directional interactions between BRCA1-IRIS-overexpression (IRISOE) tumor cells and stromal cells in generating aggressive triple negative breast cancers. Experimental Procedures: We used co-culturing assay, immunohistochemistry, in vitro invasion assay with or without cytokines neutralization, ELISA, western blot analysis, exposure to hypoxic conditions, cytokines receptor inactivation, in vivo orthotopic tumor formation assay, analysis of publically available data sets for the association of selected factors with overall survival, distant metastasis free survival and recurrent free survival to define the role of these bi-directional interactions in enhancing IRISOE tumors aggressiveness. Results: Here we show formation of an aggressiveness niche within IRIS overexpressing triple negative breast cancers (IRISOE/TNBCs) defined as the necrotic/hypoxic core. To this niche, metabolically stressed IRISOE/TNBC cells attract mesenchymal stem cells (MSCs) to the aggressiveness niche through secreting high levels of IL-1β. IL-1R-negative MSCs are induced to express the receptor upon exposure to medium conditioned by IRISOE/TNBCs. Activated by IL-1β, IL-1R activates AKT, MAPK and NF-κB signaling in MSCs to which they respond by releasing inflammatory cytokines, such as CXCL1. Inhibiting IL-1β signaling utilizing neutralizing antibody attenuates MSCs recruitment and CXCL1 secretion, in vitro and in vivo. CXCL1 receptor; CXCR2 is expressed on IRISOE/TNBCs only and thus CXCL1 acts in a paracrine fashion to entrain IRISOE/TNBCs. Mechanistically, MSCs-entrained IRISOE/TNBCs secrete CCL2 and VEGF that activate and attract tumor associated macrophages (TAMs) and endothelial cells (ECs), respectively to the vicinity of IRISOE/TNBCs in the aggressiveness niche. S100A8 and IL-8 secreted from IRISOE/TNBCs-activated TAMs and ECs, respectively in concert with CXCL1 enhance IRISOE/TNBCs aggressiveness. In pre-clinical model, IRISOE cells co-injected with MSCs (10:1 ratio) developed faster and bigger orthotopic mammary tumors containing more TAMs and ECs compared to IRISOE/TNBCs injected alone. These tumors progressed to develop spontaneous lymph-node or distant metastases (e.g., bone, lung and/or brain). Conclusion: We propose that in concert with an anti-BRCA1-IRIS drug, inhibitors to the reciprocal interactions between IRISOE/TNBCs and their surrounding stromal cells could be exploited as a viable therapy for IRISOE/TNBCs and their metastases. Citation Format: Abhilasha Sinha, Wael M. ElShamy. Aggressiveness niche within BRCA1-IRIS/TNBC tumors is supported by reciprocal interactions with the microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3868.