Abstract 1171: Proinflammatory chemokine interleukin-8 in the tumor microenvironment modulates breast cancer phenotype

Cancer growth and progression is influenced by tumor cells, stromal cells, as well as various secreted molecules found within the tumor microenvironment (TME). These secreted molecules participate in various crosstalk events that contribute to cancer development and progression. One such secreted molecule found within the tumor microenvironment is the proinflammatory cytokine interleukin-8 (IL-8). IL-8 influences cancer development by binding to its G-protein coupled receptors CXCR1 and CXCR2 in turn leading to activation of various signal transduction pathways that promotes cell proliferation, survival, angiogenesis, and invasion. We hypothesized that infiltrating macrophages and tumor cells participate in cellular crosstalk through the release of inflammatory cytokines which function to modulate the breast cancer phenotype. Using a cell culture model, conditioned media (CM) generated from activated THP-1 monocytes as well as recombinant IL-8 (rIL-8) were individually tested on the breast cancer cell lines T47D (ER +) and MDA-MB 231 (ER -) in order to evaluate cell proliferation, cell signaling pathways, invasion, and migration. Increased proliferation was observed for both T47D and MDA-MB 231 following treatment with rIL-8 as opposed to an inhibition in proliferation, which was observed following culturing of T47D and MDA-MB 231 with THP-1 CM. It is presumed that THP-1 CM contains both inhibitory and stimulatory factors, which include IL-8. Activation of the MAPK signaling pathway, as observed by phosphorylation of MEK and ERK, was modulated in response to activated THP-1 CM, which may explain the enhanced migration and invasion observed in the breast cancer cells upon treatment with rIL-8. In order to further characterize the crosstalk between THP-1 and breast cancer cells, the inverse experiments were performed by incubating non-activated THP-1 monocytes with CM generated from MDA-MB 231 cells. Interestingly, MDA-MB 231 CM was capable of activating THP-1 monocytes comparable to that of the classical activating agent phorbol diester 12-O-tetradecanoylphorbol 13-acetate (TPA). Characterization of the MDA-MB 231 CM by cytokine array analysis revealed an abundance of the proinflammatory cytokines IL-6 and IL-8 and although this needs further characterization, we believe that secretion of IL-6 and IL-8 is essential to the crosstalk between breast cancer cells and THP-1 monocytes, which modulates the breast cancer cell phenotype. Citation Format: Robert Bednarczyk, Neha Tuli, Ghada Benrahoma, Rui Kitadai, Robert Suriano, Abraham Mittelman, Raj K. Tiwari. Proinflammatory chemokine interleukin-8 in the tumor microenvironment modulates breast cancer phenotype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1171. doi:10.1158/1538-7445.AM2014-1171