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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Howcroft, Thomas K
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Bohrer, Laura R; Chaffee, Thomas S; Chuntova, Pavlina et al. (2016) ADAM17 in tumor associated leukocytes regulates inflammatory mediators and promotes mammary tumor formation. Genes Cancer 7:240-253
Brincks, Erik L; Kucaba, Tamara A; James, Britnie R et al. (2015) Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma. FEBS J 282:4747-65
Schwertfeger, Kathryn L; Cowman, Mary K; Telmer, Patrick G et al. (2015) Hyaluronan, Inflammation, and Breast Cancer Progression. Front Immunol 6:236
Farooqui, Mariya; Bohrer, Laura R; Brady, Nicholas J et al. (2015) Epiregulin contributes to breast tumorigenesis through regulating matrix metalloproteinase 1 and promoting cell survival. Mol Cancer 14:138
Bohrer, Laura R; Chuntova, Pavlina; Bade, Lindsey K et al. (2014) Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation. Cancer Res 74:374-86
Brady, Nicholas; Chuntova, Polly; Bade, Lindsey K et al. (2013) The FGF/FGFR axis as a therapeutic target in breast cancer. Expert Rev Endocrinol Metab 8:391-402
Bohrer, Laura R; Schwertfeger, Kathryn L (2012) Macrophages promote fibroblast growth factor receptor-driven tumor cell migration and invasion in a CXCR2-dependent manner. Mol Cancer Res 10:1294-305
Reed, Johanna R; Stone, Matthew D; Beadnell, Thomas C et al. (2012) Fibroblast growth factor receptor 1 activation in mammary tumor cells promotes macrophage recruitment in a CX3CL1-dependent manner. PLoS One 7:e45877
Bade, Lindsey K; Goldberg, Jodi E; Dehut, Hazel A et al. (2011) Mammary tumorigenesis induced by fibroblast growth factor receptor 1 requires activation of the epidermal growth factor receptor. J Cell Sci 124:3106-17