FGF signaling activates STAT1 and p21 and inhibits the estrogen response and proliferation of MCF-7 cells.
Normal breast tissue as well as most breast tumors are dependent on estrogen for growth. Breast tumors often progress to a hormone-independent state which is associated with poor prognosis. It has been proposed that activation of growth factor signaling pathways in the tumor cells may free them from hormonal control. Certain growth factors can mimic estrogen responses by activating the estrogen receptor via its phosphorylation by mitogen-activated protein (MAP) kinase. In this report, however, we show that fibroblast growth factor (FGF), despite activating MAP kinase, is growth-inhibitory for estrogen-dependent MCF-7 breast cancer cells. MCF-7 cells treated with FGFs exhibit slower growth than controls in both the presence and absence of estrogen, with a concomitant increase in the number of cells in G0/G1. Expression of a constitutively activated FGF receptor in these cells further decreases their growth rate, which is no longer influenced by FGF treatment. Activation of the FGF signaling pathway also reduces the induction of an estrogen-responsive CAT reporter plasmid by estrogen, an effect which appears to be independent of serine 118 in the estrogen receptor, a MAP kinase target site. The inhibitory effects of FGF are probably mediated through the sustained induction of the cyclin kinase inhibitor p21/WAF1/CIP1, which is upregulated at the mRNA and protein level by FGF. FGF treatment also results in the phosphorylation of STAT1. This upregulation of p21 and phosphorylation of STAT1 is not detectable in T47D breast cancer cells upon which FGF has no inhibitory effect.
Johnson
M R
MR
Department of Microbiology and the Kaplan Cancer Center, New York University School of Medicine, NY 10016, USA.
Valentine
C
C
Basilico
C
C
Mansukhani
A
A
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism* / Q000473:pathology; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D004967:Estrogens; D017468:Receptors, Fibroblast Growth Factor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D005346:Fibroblast Growth Factors; D017871:Calcium-Calmodulin-Dependent Protein Kinases