The Role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression

Abstract

A growing body of evidence indicates that interactions between neoplastic cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are crucial in promoting tumor cell invasion and progression. Macrophages play an ambiguous role in these processes since this M1 phenotype correlates with tumoricidal capacity whereas TAMs of M2 phenotype exert tumor-promoting effects. Here, we provide evidence that interactions between mouse breast tumor cells and TAMs remodel the TME, leading to upregulation of Fra-1, a member of the FOS family of transcription factor. In turn, this proto-oncogene initiates activation of the IL-6/JAK/Stat3 signaling pathway. This creates a malignant switch in breast tumor cells, leading to increased release of pro-angiogenic factors MMP-9, VEGF and TGF-β from tumor cells and intensified invasion and progression of breast cancer. Proof of concept for the crucial role played by transcription factor Fra-1 in regulating these processes was established by specific knockdown of Fra-1 with siRNA which resulted in marked suppression of tumor cell invasion, angiogenesis and metastasis in a mouse breast cancer model. Such a strategy could eventually lead to future efficacious treatments of metastatic breast cancer.