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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA132827-01A1
Application #
8102676
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Howcroft, Thomas K
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
1
Fiscal Year
2011
Total Cost
$313,325
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Knutson, Todd P; Truong, Thu H; Ma, Shihong et al. (2017) Posttranslationally modified progesterone receptors direct ligand-specific expression of breast cancer stem cell-associated gene programs. J Hematol Oncol 10:89
Brady, Nicholas J; Farrar, Michael A; Schwertfeger, Kathryn L (2017) STAT5 deletion in macrophages alters ductal elongation and branching during mammary gland development. Dev Biol 428:232-244
Girard, Brian J; Knutson, Todd P; Kuker, Bethanie et al. (2017) Cytoplasmic Localization of Proline, Glutamic Acid, Leucine-rich Protein 1 (PELP1) Induces Breast Epithelial Cell Migration through Up-regulation of Inhibitor of ?B Kinase ? and Inflammatory Cross-talk with Macrophages. J Biol Chem 292:339-350
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
Brady, Nicholas J; Chuntova, Pavlina; Schwertfeger, Kathryn L (2016) Macrophages: Regulators of the Inflammatory Microenvironment during Mammary Gland Development and Breast Cancer. Mediators Inflamm 2016:4549676
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
Cowman, Mary K; Lee, Hong-Gee; Schwertfeger, Kathryn L et al. (2015) The Content and Size of Hyaluronan in Biological Fluids and Tissues. Front Immunol 6:261
Schwertfeger, Kathryn L; Cowman, Mary K; Telmer, Patrick G et al. (2015) Hyaluronan, Inflammation, and Breast Cancer Progression. Front Immunol 6:236
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 282:4747-4765
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

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