Activation of the IL-6/JAK/STAT3 signaling pathway via up-regulation of Fra-1 in tumor associated macrophages represents a malignant switch in breast carcinoma invasion and metastasis

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Interactions between neoplastic and stromal cells contribute to tumor progression. Fos-related antigen-1 (Fra-1) and Interleukin 6 (IL-6), which are involved in tumor cell angiogenesis, invasion and metastasis are often deregulated in cancer and serve as attractive candidates to regulate these effects. Here, we demonstrate that Fra-1 up-regulation in tumor associated macrophages (TAMs) functions as a malignant switch in breast carcinoma via deregulation of the IL-6/Stat3 signaling pathway and increases the release of MMP9, VEGF and TGF-β. Co-culture of murine 4T1 breast cancer cells with TAMs leads to up-regulation of Fra-1, IL-6 and Stat3 in TAMs. High levels of Fra-1, IL-6 and Stat3 were also detectable in TAMs in primary breast cancer tissue. Furthermore, the Fra-1 blockade in TAMs is able to down-regulate IL-6, Stat3 and decreases the release of MMP9, VEGF and TGF-β. This, in turn, results in suppression of angiogenesis, invasion, growth and metastasis of 4T1 breast carcinoma cells in the tumor microenvironment.