Expression and Function of Fgf-8 During Murine Mammary Gland Development and Tumorigenesis
Abstract
Fibroblast growth factors consist of a family of ligands and tyrosine kinase receptors that are potent regulators of branching morphogenesis, organogenesis, and angiogenesis. We have constructed and characterized chimeric proteins that contain the intracellular kinase domain of FGFR1 linked to a modified FK506-binding protein. These chimeric proteins can be induced to homodimerize in the presence of the lipid soluble drug AP2O187 87. The validity of this system was tested in the HCl1 1 mammary epithelial cell line and in transgenic mouse models using a MMTV transgene cassette. In the mammary gland of transgenic mice treated with AP20187, a fifteen-fold increase in proliferation, activation of MAPK and AKT and a marked increase in lateral budding was observed when compared with wild-type littermates. Initial lateral buds appear after ten days of AP2O187 treatment and consist of a single layer of epithelial cells retaining apical and basolateral polarity. After 2-4 weeks of AP20187 treatment, increasingly invasive lesions appeared with multi-cell layered lateral buds, loss of myoepithelium, increased vasculature branching and loss of cell polarity. These data suggest that short term FGFR1 kinase signaling can increase lateral budding of the mammary epithelium and sustained activation of this pathway results in alveolar hyperplasia and invasive lesions. We have developed an inducible system to study FGFR1 signaling in the mammary gland that will be useful in elucidating the role of these receptors in branching morphogenesis and provide a model system to understand early events in transformation
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2001
- Accession Number
- ADB274568
Entities
People
- Bryan Welm
- Jeffrey M. Rosen
Organizations
- Baylor College of Medicine