Reed, Johanna Rae2013-07-292013-07-292012-06https://hdl.handle.net/11299/154196University of Minnesota Ph.D. dissertation. June 2012. Major: Microbiology, Immunology and Cancer Biology. Advisor: Dr. Kathryn L. (Kaylee) Schwertfeger. 1 computer file (PDF); xii, 147 pages.Tumor formation is an extensive process requiring complex interactions that involve both tumor cell-intrinsic pathways and soluble mediators within the microenvironment. Tumor cells exploit the intrinsic functions of many soluble molecules, including cytokines and chemokines and their receptors, to regulate pro-tumorigenic phenotypes that are required for development of the primary tumor. Previous studies demonstrated that activation of inducible FGFR1 (iFGFR1) in mammary epithelial cells resulted in increased proliferation, migration, and invasion in vitro and tumor formation in vivo. Early studies also indicated that iFGFR1 activation stimulated recruitment of macrophages to the epithelium resulting in increased epithelial cell proliferation and angiogenesis. Our current studies further examined this model to identify novel mechanisms that regulate early stage tumorigenesis with a specific emphasis on the soluble mediators that are regulated by iFGFR1 to promote epithelial and stromal cell migration. Results from this study elucidate a novel role for iFGFR1-induced osteopontin in promoting a proinflammatory tumor microenvironment through the regulation of proinflammatory molecules such as IL-1beta; and activation of the COX-2/PGE2 pathway as well as by promoting recruitment of CX3CR1-expressing macrophages through regulation of the chemokine CX3CL1. Defining the role of osteopontin-regulated proinflammatory, secreted molecules in promoting iFGFR1-mediated mammary tumorigenesis is important for understanding how initiating oncogenic events drive tumor growth and progression through the secretion of soluble mediators. Moreover, results from these studies will aid in identifying potential novel molecular targets for therapeutic intervention.en-USBreast cancerCell migrationCX3CL1FGFR1IL-1betaOsteopontinThesis or Dissertation