Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins.
Overexpression of fibroblast growth factor receptor (FGFR) tyrosine kinases has been found in many human breast cancers and has been associated with poor patient prognosis. In order to understand the mechanism by which FGFR mediates breast cancer cell proliferation, we used a low molecular weight compound, PD173074, that selectively inhibits FGFR tyrosine kinase activity and autophosphorylation. This potential anticancer agent caused a G1 growth arrest of MDA-MB-415, MDA-MB-453 and SUM 52 breast cancer cells. Our analyses revealed that FGFR signaling links to the cell cycle machinery via D-type cyclins. PD173074-mediated inhibition of FGFR activity caused downregulation of cyclin D1 and cyclin D2 expression, inhibition of cyclin D/cdk4 activity and, as a consequence, reduction of pRB phosphorylation. Retroviral-mediated ectopic expression of cyclin D1 prevented pRB hypophosphorylation and the cell cycle G1 block in PD173074-treated cells, suggesting a central role for D cyclins in proliferation of FGFR-driven breast cancer cells. The repression of FGFR activity caused downregulation of MAPK in MDA-MB-415 and MDA-MB-453 cells. In SUM 52 cells, both MAPK and PI3K signaling pathways were suppressed. In conclusion, results shown here describe a mechanism by which FGFR promotes proliferation of breast cancer cells.
Koziczak
Magdalena
M
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Holbro
Thomas
T
Hynes
Nancy E
NE
D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D056741:Cyclin D; D016213:Cyclins; C115711:PD 173074; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor