FGF signaling activates STAT1 and p21 and inhibits the estrogen response and proliferation of MCF-7 cells

Abstract

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 ®broblast growth factor (FGF), despite activating MAP kinase, is growthinhibitory 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 in¯uenced by FGF treatment. Activation of the FGF signaling pathway also reduces the induction of an estrogen-responsive CAT reporter plasmid by estrogen, an e ect which appears to be independent of serine 118 in the estrogen receptor, a MAP kinase target site. The inhibitory e ects 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 e ect.

Anti-sense oligonucleotide of p21(waf1/cip1) prevents Interleukin 4-mediated elevation of p27(kip1) in low grade astrocytoma cells

“…STAT6 binding sites have been found in promoter regions of several IL-4-inducible genes (Kotanides and Reich, 1996;Lu et al, 1997). Binding sites for STAT1, another member of the STAT family, have been detected within the p21(waf1/cip1) promoter region, and activation of STAT1 and p21(waf1/cip1) are linked in some cells growth-arrested by EGF or ®broblast growth factor (Chin et al, 1996;Johnson et al, 1998). Interestingly, a DNA sequence recognized by STAT1 (TTC{N 3 }GAA) can also be bound by STAT6 (Seidel et al, 1995).…”

Basic fibroblast growth factor (bFGF)-induced cell death is mediated through a caspase-dependent and p53-independent cell death receptor pathway

“…Our previous studies have shown induction of death in EWS-FLI1 type 2 containing RD-ES cells (Sturla et al, 2000). Furthermore, bFGF decreases cell proliferation (Wang et al, 1997;Johnson et al, 1998) and induces cell death (Burchill, unpublished observation) in the breast cancer cell line MCF7, which does not contain an EWS-ETS gene rearrangement (Burchill, unpublished observations). These observations are consistent with the hypothesis that EWS-ETS fusion protein is not involved in the mechanism of bFGF-induced cell death.…”

Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations

“…Since various pathways (such as those involving MAPK and STATs) seem to mediate FGFR3 activation in di erent cell systems (Legeai-Mallet et al, 1998;Ra oni et al, 1998;Johnson et al, 1998;CatlettFalcone et al, 1999;Hart et al, 2000; for review see Kannan and Givol, 2000), we analysed the downstream e ects of FGFR3 expression in our MM cell lines. Using an in vivo phosphorylation assay, we evaluated the activation of MAPK, STAT1 and STAT3.…”