C/EBPβ at the core of the TGFβ cytostatic response and its evasion in metastatic breast cancer cells

SummaryBreast cancers may evade the growth-inhibitory action of TGFβ by accumulating defects of unknown nature that selectively eliminate cytostatic gene responses. We found the transcription factor C/EBPβ to be essential for TGFβ induction of the cell cycle inhibitor p15INK4b by a FoxO-Smad complex and repression of c-MYC by an E2F4/5-Smad complex in human epithelial cells. These cytostatic responses are selectively missing in metastatic breast cancer cells from half of the patients that we tested. The basis for this loss was traced to an excess of the C/EBPβ inhibitory isoform LIP. We suggest that C/EBPβ plays a key role in the coordination of TGFβ cytostatic gene responses, and its malfunction may trigger evasion of these responses in breast cancer.