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 es trogen for growth, Breast tumors often progress to a hormone-independe nt state which is associated with poor prognosis, It has been proposed that activation of growth factor signaling pathways in the tumor cell s may free them from hormonal control. Certain growth factors can mimi c estrogen responses by activating the estrogen receptor via its phosp horylation by mitogen-activated protein (MAP) kinase, In this report, however, we show that fibroblast growth factor (FGF), despite activati ng MAP kinase, is growth-inhibitory for estrogen-dependent MCF-7 breas t cancer cells, MCF-7 cells treated with FGFs exhibit slower growth th an controls in both the presence and absence of estrogen, with a conco mitant increase in the number of cells in G0/G1, Expression of a const itutively activated FGF receptor in these cells further decreases thei r growth rate, which is no longer influenced by FGF treatment. Activat ion of the FGF signaling pathway also reduces the induction of an estr ogen-responsive CAT reporter plasmid by estrogen, an effect which appe ars to be independent of serine 118 in the estrogen receptor, a MAP ki nase target site. The inhibitory effects of FGF are probably mediated through the sustained induction of the cyclin kinase inhibitor p21/WAF 1/CIP1, which is upregulated at the mRNA and protein level by FGF, FGF treatment also results in the phosphorylation of STAT1, This upregula tion of p21 and phosphorylation of STAT1 is not detectable in T47D bre ast cancer cells upon which FGF has no inhibitory effect.