Expression and Function of Fgf-8 During Murine Mammary Gland Development and Tumorigenesis

摘要

Fibroblast growth factors (FGF) have been shown by gain and loss of function experiments to play critical roles in development and tumorigenesis. FGEs are expressed during all stages of mouse mammary gland development and in humans dysregulated expression has been correlated with poor prognosis breast cancer. The focus of this research is to study how FGEs function during mammary gland development and what role they play in the etiology of breast cancer. We have developed and characterized a system of FGE-independent inducible activation of fibroblast growth factor receptors (FGER) . The intracellular kinase domains of all four FGERs have been cloned together with a EVBP domain that can induce dimerization in the presence of the lipid soluble drug AP20l87. NIH3T3 fibroblasts stably transfected with the FGER- EVBP constructs can be AP20l87-dependently rescued from serum deprivation induced apoptosis as measured by MTS and caspase-3 activation assays. Dimerization of FGER- FVBPs leads to phosphorylation of themselves and downstream signaling factors including ERKl/2 and AKT. Anti-apoptotic Pol family members Bcl2 and Bcl-xl mRNA are upregulated by FGFR-FVBP activation. From these data we propose that FGFRs can block apoptosis in NIH3T3 cells through post-translational and transcriptional pathways. Transgenic mice that express these constructs in the mammary gland are currently being characterized.