CSF-1 activates MAPK-dependent and p53-independent pathways to induce growth arrest of hormone-dependent human breast cancer cells

Abstract

The CSF-1 receptor (CSF-1R) is expressed in 450% of human breast cancers. To investigate the consequence of CSF-1R expression, hormone-dependent human breast cancer cell lines, MCF-7 and T-47D, were transfected with CSF-1R. Unexpectedly, CSF-1 substantially inhibited estradiol (E 2 ) and insulin-dependent proliferation of MCF-7 transfectants (MCF-7fms) and prevented cyclin E/cdk2 and cyclin A/cdk2 activation, consistent with a G 1 arrest. In contrast, CSF-1 increased DNA synthesis in T-47D transfectants (T-47Dfms) alone and with E 2 or insulin. In response to CSF-1, there was a marked and sustained upregulation of the cyclindependent kinase inhibitor, p21, in MCF-7fms but not T-47Dfms. CSF-1 also markedly upregulated cyclin D1 in MCF-7fms. The coordinate increase in cyclin D1 and p21 had the eect of decreasing the speci®c but not absolute activity of cyclin D1/cdk4. p53 was not involved since CSF-1 induction of p21 was unaected by dominant-negative p53 expression. ERK activation by CSF-1 was robust and sustained in MCF7fms and to a much lesser extent in T-47Dfms. Using pharmacological and transient transfection approaches, we showed that ERK activation was necessary and sucient for p21 induction in MCF-7fms. Moreover, activated MEK inhibited E 2 -stimulated cdk2 activity. Our ®ndings indicate that the consequence of CSF-1R-mediated signals in human breast cancer cells is dependent on the genetic background of the particular tumor.

Both Src-Dependent and -Independent Mechanisms Mediate Phosphatidylinositol 3-Kinase Regulation of Colony-Stimulating Factor 1-Activated Mitogen-Activated Protein Kinases in Myeloid Progenitors

“…Waf1 (49). Such disparate behavior illustrates the now well-documented concept that cellular context plays an important role in determining outcome of ERK activation (reviewed in reference 53).…”

Gab2 Promotes Colony-Stimulating Factor 1-Regulated Macrophage Expansion via Alternate Effectors at Different Stages of Development

“…11h). Although persistent CSF-1-induced Erk activity can lead to cell cycle arrest (30), inhibition of Erk activity resulted in diminished proliferation in both WT and Gab2 Ϫ/Ϫ BMMs (Fig. 11i).…”

Growth and cell cycle regulation by isoflavones in human breast carcinoma cells

“…The estrogenic effects of isoflavones include binding to the estrogen receptor (ER) or the type II estradiol (E2)-binding site [18,19], promotion of proliferation of reproductive organs in animals [39], induction of pS2 protein expression [29] and stimulation of growth in estrogen-dependent human breast cancer cells [12,13,37]. Suggested antiestrogenic effects include competition with E2 for binding to the ER [34], reduction of estrogen synthesis via the inhibition of aromatase activity [1], down-regulation of E2-induced expression of ER and the pS2 protein in MCF-7 cells [14,38], and inhibition of E2-induced growth in breast cancer cells [12,13,25].…”