Fibroblast growth factor 8 induced downregulation of thrombospondin 1 is mediated by the MEK/ERK and PI3K pathways in breast cancer cells

Abstract

Expression of fibroblast growth factor 8 (FGF-8) is increased in several forms of hormonal cancer. It was previously shown to regulate expression of thrombospondin 1 (TSP-1), an inhibitor of angiogenesis, in S115 breast cancer cells. Here, we studied the FGF-8-activated signalling pathways mediating TSP-1 repression in S115 cells and in non-tumorigenic MCF10A cells. Inhibition of FGF receptors or of MEK1/2 and PI3K with specific inhibitors (PD173074, U0126 or LY294002, respectively) restored TSP-1 mRNA expression in the presence of FGF-8 in S115 cells. Furthermore, U0126 and LY294002 increased TSP-1 mRNA expression in S115 cells over-expressing FGF-8. In MCF10A cells, FGF-8 treatment also decreased TSP-1 expression and the effect was dependent on active MEK1/2. In conclusion, FGF-8 suppresses TSP-1 expression through two independent pathways, MEK1/2 and PI3K. Repression of TSP-1 may be an important mechanism involved in induction of an angiogenic phenotype and growth of FGF-8-expressing breast cancer.

Keywords::

• Fibroblast growth factors
• breast cancer cells
• mitogen-activated kinases
• thrombospondin
• angiogenesis

Acknowledgements

Ms Soili Jussila is warmly thanked for technical assistance. K. Tarkkonen is a student of Turku Graduate School of Biomedical Science.

Declaration of interest: This research was supported by the Finnish Cancer Institute, Finnish Cultural Foundation and the Sigrid Juselius Foundation. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.