Spatiotemporal regulation of DNp63 by TGFb-regulated miRNAs is essential for cancer metastasis

Abstract

DNp63 is a transcription factor of the p53 family and has crucial functions in normal development and disease. The expression pattern of DNp63 in human cancer suggests dynamic regulation of this isoform during cancer progression and metastasis. Many primary and metastatic tumors express high levels of DNp63, while DNp63 loss is crucial for tumor dissemination, indicating an oscillatory expression of DNp63 during cancer progression. Here, we use genetically engineered orthotopic mouse models of breast cancer to show that while depletion of DNp63 inhibits primary mammary adenocarcinoma development, oscillatory expression of DNp63 in established tumors is crucial for metastatic dissemination in breast cancer. A TGFb-regulated miRNA network acted as upstream regulators of this oscillatory expression of DNp63 during cancer progression. This work sheds light on the pleiotropic roles of DNp63 in cancer and unveils critical functions of TGFb in the metastatic process.