The Role of FGFR1 Signaling in Mammary Gland Development, Stem Cell Self-Renewal and Tumorogenesis

The fibroblast growth factor (FGF) signaling pathway is a highly conserved family of four receptor tyrosine kinases, FGFR1-4 and at least 22 secreted FGF ligands.  Each FGF ligand can selectively bind to and activate on or more of the four FGF receptors, making the pathway highly complex, redundant and very hard to study.  Intracellular FGF-FGFR signaling is known to dictate many of the processes involved in embryonic development, tissue homeostasis and angiogenesis with alterations in its signaling leading to many developmental defects and disease states, including cancer.  In fact, recent findings show the FGF signaling pathway to contain the highest enrichment of kinases containing driver mutations that are positively selected for in a diverse cross section of human cancers, including breast cancer.  Despite FGFR1s role in breast cancer, little is known about both its function in normal mammary gland development and tumorogenesis.  FGFR1 signaling has been also been shown to be important in stem cell self-renewal in several tissues and embryonic stem cells.  Due to the quickly growing field of cancer stem cells, it is interesting to speculate about the importance of FGFR1 signaling in both the maintenance of the stem/progenitor pool in the normal mammary gland and the expansion of tumor stem cells.  My project goals consist of the three aims; 1) Investigate the effect of conditional FGFR1 loss on embryonic and postnatal mammary gland development, 2) Investigate the role of FGFR1 signaling in mammary stem cell self-renewal and 3) Investigate the role of FGFR1 signaling in tumor initiation, growth and tumor stem cell self-renewal in a Wnt-1 overexpression tumor model.  These studies should provide a through investigation of FGFR1 and its role in normal mammary gland development and cancer initiation.