Tyrosine kinase signalling in breast cancer: fibroblast growth factors and their receptors

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.

Figure 1

Fgf receptor structure and Fgf signalling. Structural domains of an Fgf receptor are shown on the right of the panel. Fgf signal transduction is initiated upon binding the Fgf ligand in conjunction with heparan sulphate to form a ternary complex. The result is autophosphorylation and activation of the tyrosine kinase, which facilitates second messenger signalling through phosphotyrosine-dependent and -independent interactions with the cytoplasmic portion of the receptor.

Figure 2

Proto-oncogene activation by insertional mutagenesis of MMTV. (a) Insertion of viral genomic DNA into somatic cellular DNA in close proximity of a silent oncogene. (b) Inserted proviral DNA induces the transcription of the oncogene.