Inflammation within the tumor microenvironment correlates with increased invasiveness and poor prognosis in many types of cancer, including breast cancer. Immune cells promote breast cancer cell invasion both in vitro and in vivo, implicating these tumor-stromal cell interactions in metastatic disease progression. Specifically, the presence of macrophages in breast carcinomas has been linked to angiogenesis, metastasis and poor prognosis. At present, however, little is known about how macrophages and inflammatory processes contribute to breast cancer initiation. Studies using a novel mouse model of mammary tumorigenesis have demonstrated that activation of the fibroblast growth factor receptor 1 (FGFR1) oncogene results in a dramatic inflammatory response within the mammary gland. Specifically, macrophages have been shown to play a causal role in the formation of FGFR1-mediated preneoplastic lesions in the mammary gland. The use of both in vitro and in vivo models has led to the identification of inflammatory mediators that contribute to pro-tumorigenic epithelial cell/macrophage interactions. These studies have led to the hypothesis that FGFR1 induces expression of the inflammatory cytokine interleukin-1 beta (IL-1), leading to a cascade of events involving induction of the protease Adam17 and shedding of epiregulin, which then acts on the macrophages to induce a tumor associated macrophage phenotype. The following specific aims are proposed: 1) Define the mechanisms that regulate epithelial cell induction and shedding of Ereg, a novel downstream target of mammary tumor-associated inflammation. 2) Evaluate the ability of mammary epithelial cell-derived Ereg to regulate macrophage activity using in vitro and in vivo models. 3) Determine the importance of the ErbB4/Stat5 signaling pathway in stimulating the tumor associated macrophage phenotype. The significance of these studies is that they will further define macrophage function during early stages of tumor formation, leading to the identification of novel markers that can be used in both diagnosis and treatment of early-stage breast tumors. In the longer term, patients at high risk for breast cancer may benefit from specific anti-inflammatory therapies that could be used to inhibit tumor formation and progression.
The proposed studies focus on understanding the role of inflammation, with a specific emphasis on macrophages, in promoting breast cancer initiation. This research is relevant to human health because understanding the mechanisms underlying the initiation and promotion of human breast cancer will ultimately lead to the development of novel therapeutic strategies for high risk and early-stage breast cancer patients.
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