Abstract
The fibroblast growth factors [Fgfs (murine), FGFs (human)] constitute a large family of ligands that signal through a class of cell-surface tyrosine kinase receptors. Fgf signalling has been associated in vitro with cellular differentiation as well as mitogenic and motogenic responses. In vivo, Fgfs are critical for animal development, and some have potent angiogenic properties. Several Fgfs have been identified as oncogenes in murine mammary cancer, where their deregulation is associated with proviral insertions of the mouse mammary tumour virus (MMTV). Thus, in some mammary tumours of MMTV-infected mouse strains, integration of viral genomic DNA into the somatic DNA of mammary epithelial cells was found to have caused the inappropriate expression of members of this family of growth factors. Although examination of human breast cancers has shown an altered expression of FGFs or of their receptors in some tumours, their role in the causation of breast disease is unclear and remains controversial.
Highlights
There is a long history linking the inappropriate expression of Fgfs with breast cancer development
Upon binding of the ligand, it appears that the Fgf receptor complexes dimerize, in conjunction with a heparan sulphate moiety, and the tyrosine kinase is activated through autophosphorylation [18]
Studies to date clearly show that inappropriate Fgf signalling in the mouse mammary gland leads to hyperplastic growth and eventually to frank neoplasia
Summary
There is a long history linking the inappropriate expression of Fgfs with breast cancer development. Upon binding of the ligand, it appears that the Fgf receptor complexes dimerize, in conjunction with a heparan sulphate moiety, and the tyrosine kinase is activated through autophosphorylation [18] These events facilitate the binding of second messenger proteins, which in turn activate various intracellular signalling pathways (for review [4]). The viral DNA appears to integrate in an essentially random manner, so that only on rare occasions does it cause a mutation that leads to a growth advantage for an infected cell, with the potential for it to progress to frank neoplasia (Fig. 2) Such events are likely to be extremely rare for any individually infected cell, but very large numbers of cells in the mouse mammary gland become infected, so most female mice will by chance eventually contain a cell that has acquired an oncogenic mutation. Oncogenes identified as common targets for activation by MMTV in mouse mammary tumours
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