The Role of Basic Fibroblast Growth Factor in Human Breast Cancer.

We found that basic fibroblast growth factor bFGF, a mitogen, inhibits human breast cancer cell lines. In MCF-7 cells, bFGF binds high-affinity tyrosine kinase FGF receptors FGFR, activates MAP kinase, induces higher levels of G1 cyclins D1 and E and cyclin dependent kinase cdk 4, but causes G1 cycle arrest through induction of cdk inhibitor p2lWAFlCIPl 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-7NCF secreted all forms and could not bind exogenous 18 kD bFGOF. They were arrested in G1, had constitutive heterodimerization between FGFR1 and FGFR4, did not phosphorylate MAP kinase, had the same levels of cyclins D1 and E, cdk4 and p21WAFlCIPl as controls, did not inactivate cdk2 nor dephosphorylate Rb. They contained inhibitory activity in a cyclin kinase assay and had elevated levels of p27klpl. Exogenous bFGF incrementally inhibited MCF-7 cells expressing only 18 kD bFGF, did not increase a constitutive phosphorylation of MAP kinase but raised intracellular p21WAP1CIP1 The data define different roles for different bFGF moieties in breast cancer.