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

The CSF-1 receptor (CSF-1R) is expressed in >50% of human breast cancers. T o investigate the consequence of CSF-1R expression, hormone-dependent human breast cancer cell lines, MCF-7 and T-47D, were transfected with CSF-1R, U nexpectedly, CSF-1 substantially inhibited estradiol (E-2) and insulin-depe ndent proliferation of MCF-7 transfectants (MCF-7fms) and prevented cyclin E/cdk2 and cyclin A/cdk2 activation, consistent with a G(1) arrest. In cont rast, 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 sust ained upregulation of the cyclin-dependent kinase inhibitor, p21(Waf1/Cip1) , in MCF-7fms but not T-47Dfms, CSF-1 also markedly upregulated cyclin D1 i n MCF-7fms, The coordinate increase in cyclin D1 and p21 had the effect of decreasing the specific but not absolute activity of cyclin D1/cdk4, p53 wa s not involved since CSF-I induction of p21 was unaffected by dominant-nega tive p53 expression. ERK activation by CSF-1 was robust and sustained in MC F-7fms and to a much lesser extent in T-47Dfms. Using pharmacological and t ransient transfection approaches, we showed that ERK activation was necessa ry and sufficient for p21 induction in MCF-7fms, Moreover, activated MEK in hibited E-2-stimulated cdk2 activity. Our findings indicate that the conseq uence of CSF-1R-mediated signals in human breast cancer cells is dependent on the genetic background of the particular tumor.