Abstract 1914: Cross-talk between breast cancer cells and tumor-associated macrophages leads to tumor cell invasion, angiogenesis and metastasis

Abstract

Abstract Interactions between neoplastic and stromal cells leads to crosstalk that contributes to tumor growth and progression. Since Fos-related antigen-1 (Fra-1) and Interleukin 6 (IL-6) are involved in tumor cell angiogenesis, invasion and metastasis, and are frequently deregulated in cancer cells, they represent attractive targets to regulate these effects. Here, we demonstrate that up-regulation of Fra-1 by tumor associated macrophages (TAMs) represents a malignant switch in breast carcinoma triggered by the deregulation of the IL-6/JAK/Stat3 signaling pathway which, in turn, increases the release of pro-angiogenesis factors MMP9, VEGF and TGF-β. Co-culture of 4T1 breast cancer cells with TAMs leads to up-regulation of Fra-1, IL-6 and Stat3 in TAMs. Furthermore, knockdown of Fra-1 in TAMs causes downregulation of IL-6, Stat3 and decreases the release of MMP9, VEGF and TGF-β. Together, these effects suppress the malignant characteristics of 4T1 breast tumor cells such as invasiveness, angiogenesis and metastasis. This study delineates novel mechanisms involved in the transcriptional deregulation of Fra-1 that lead to the activation of the IL-6/JAK/Stat3 signaling pathway in TAMs. Such events play a key role in promoting breast cancer cell invasion, growth and metastasis and our findings will determine if AP-1 family transcription factors such as Fra-1 are responsible for the overexpression of IL-6 in TAMs. Importantly, blocking of the IL-6/JAK/Stat3 signaling pathway will interrupt the crosstalk between TAMs and breast tumor cells in the tumor microenvironment (TME) and thereby change the biological function of TAMs, resulting in the suppression of breast cancer invasion and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1914.