Oncostatin M induces growth arrest of mammary epithelium via a CCAAT/enhancer-binding protein delta-dependent pathway

Oncostatin M (OSM), an interleukin 6-type cytokine, induces sustained up-regulation of CCAAT/enhancer-binding protein (C/EBP) delta mRNA and protein in nonneoplastic HC11 mouse mammary epithelial cells. This up-regulation is dependent on signaling by phospho-Stat3 (signal transducers and activators of transcription). The same signaling pathway is activated in two human breast cancer cell lines, a neoplastic mouse mammary epithelial cell line and a second nonneoplastic mouse mammary epithelial cell line. [3H]Thymidine incorporation and flow cytometry demonstrate that OSM inhibits the growth of HC11 cells by reducing the number of S-phase cells. These phenotypic changes are accompanied by reduced expression of S-phase genes with a corresponding increased expression of G0 genes in HC11 cells. Reduction of C/EBPdelta protein in HC11 cells by expression of a C/EBPdelta antisense construct inhibits OSM-mediated growth arrest. These data demonstrate that OSM induces up-regulation of C/EBPdelta via a Stat3-dependent pathway in mammary epithelial cells and that the growth inhibition induced by OSM depends on the presence of C/EBPdelta.