Abstract 430: MCP-1/CCL2 and IL-8 regulate proteolytic activity of triple negative inflammatory breast cancer via cathepsin B, ERK1/2, JAK1 and Src signaling pathways

Background Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Recently, we have shown that macrophages isolated from the tumor microenvironment of IBC patients secrete monocyte chemoattractant protein-1/CC-chemokine ligand 2 (MCP-1/CCL2) and IL-8 that augment dissemination and metastasis of IB carcinoma cells. However, the precise molecular mechanism by which these cytokines exert their effect is still unclear. Methods In the present study, the triple negative breast cancer (TNBC) cell lines Sum149 (IBC) and HCC70 (non-IBC) cells were employed to analyze the effect of IL-8 and MCP-1/CCL2 on the proteolytic activity using live cell imaging assay, expression of cathepsin B and the activation status of STAT3, AKT, JAK1 and Src. In addition, we enrolled TNBC patients sub-grouped into IBC (n = 15), non-IBC (n = 19) patients. Results Our results revealed that upon stimulation with MCP-1/CCL2 and IL-8, Sum149 cells and HCC70 exhibited an increase in DQ-collagen degradation-mediated proteolytic activity. Mechanistically, MCP-1/CCL2 and IL-8 increase collagen degradation via enhanced expression of cathepsin B single chain mature enzyme (31 kDa) and the heavy chain of double chain mature enzyme (25/26 kDa). Moreover, MCP-1/CCL2 and IL-8 enhance activation of STAT3, ERK1/2 and AKT in both Sum149 and HCC70 cells. Interestingly, we detected over-expression of cathepsin B in the carcinoma tissues of TNBC-IBC patients compared to non-IBC patients. Over expression of cathepsin B found to be associated with activation of Src and ERK1/2, in IBC as compared to non-IBC tissues. Conclusions Our data indicate that MCP-1/CCL2 and IL-8 stimulate proteolytic activity, cathepsin B expression and Src-ERK1/2 pathway in IBC tissues versus non-IBC. Targeting MCP-1/CCL2 and IL-8 in triple negative IBC patients represents a promising therapeutic strategy. Citation Format: Sherif A. Ibrahim, Eslam A. Elghonaimy, Mohamed El-Shinawi, Medhat El-Halawany, Mohamed A. Nouh, Tahani El-Mamlouk, Bonnie F. Sloane, Mona Mostafa Mohamed. MCP-1/CCL2 and IL-8 regulate proteolytic activity of triple negative inflammatory breast cancer via cathepsin B, ERK1/2, JAK1 and Src signaling pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 430. doi:10.1158/1538-7445.AM2015-430