Role of Basic Fibroblast Growth Factor in Human Breast Cancer

摘要

We found that basic fibroblast growth factor (bFGF), a mitogen, inhibits humanbreast cancer cell lines. In MCF-7 cells, bFGF binds high-affinity tyrosine kinase FGF receptors (FGFR), activates MAP kinase, induces higher levels of G(1) cyclins D1 and E and cyclin dependent kinase (cdk) 4, but causes G(1) cycle arrest through induction of cdk inhibitor p2l(WAFl/CIPl) FGF increases association of p21 with complexes of cyclins D1 and E, inactivates cdk2 and dephosphorylates retinoblastoma protein (Rb). FGF inhibits other mammary cell lines, but only if they do not contain cytoplasmic (18 kD) and nuclear localizing (22 and 24kD) bFGF. MCF-7 cells engineered to express all three bFOF moieties (MCF-7/NCF) secreted all forms and could not bind exogenous 18 kD bFGOF. They were arrested in G(1), had constitutive heterodimerization between FGFR1 and FGFR4, did not phosphorylate MAP kinase, had the same levels of cyclins D1 and E, cdk4 and p21(WAFl/CIPl) as controls, did not inactivate cdk2 nor dephosphorylate Rb. They contained inhibitory activity in a cyclin kinase assay and had elevated levels of p27(klpl). Exogenous bFGF incrementally inhibited MCF-7 cells expressing only 18 kD bFGF, did not increase a constitutive phosphorylation of MAP kinase but raised intracellular p21(WAP1/CIP1) The data define different roles for different bFGF moieties in breast cancer.