Negative regulation of fibroblast growth factor 10 (FGF-10) by polyoma enhancer activator 3 (PEA3)

FGF-10 plays an important role in development and disease, acting as the key ligand for FGFR2B to regulate cell proliferation, migration and differentiation. Aberrant FGF signalling is implicated in tumourigenesis, with several cancer studies reporting FGF-10 or FGFR2B upregulation or identifying activating mutations in Fgfr2. We used 5’ RACE to identify a novel transcription start site for murine Fgf-10. Conventional in silico analysis predicted multiple binding sites for the transcription factor PEA3 upstream of this site. Binding was confirmed by chromatin immunopreciptation, and functional significance was studied by both RNAi knockdown and transient over-expression of PEA3. Knockdown of PEA3 message led to increased Fgf-10 expression, whereas overexpression of PEA3 resulted in decreased Fgf-10 expression. Thus, we have identified PEA3 as a negative regulator of Fgf-10 expression in a murine cell line and confirmed that activity also is seen in human breast cancer cell lines (MCF-7 and MDA-MB-231). Furthermore, over-expression of PEA3 in these cells resulted in impaired cell migration, which was rescued by treatment with FGF-10. Thus, PEA3 can regulate the transcription of Fgf-10 and such modulation can control breast cancer cell behaviour.