Spatiotemporal Regulation of ?Np63 by TGF?-Regulated miRNAs Is Essential for Cancer Metastasis.

ABSTRACT: ?Np63 is a transcription factor of the p53 family and has crucial functions in normal development and disease. The expression pattern of ?Np63 in human cancer suggests dynamic regulation of this isoform during cancer progression and metastasis. Many primary and metastatic tumors express high levels of ?Np63, while ?Np63 loss is crucial for tumor dissemination, indicating an oscillatory expression of ?Np63 during cancer progression. Here, we use genetically engineered orthotopic mouse models of breast cancer to show that while depletion of ?Np63 inhibits primary mammary adenocarcinoma development, oscillatory expression of ?Np63 in established tumors is crucial for metastatic dissemination in breast cancer. A TGF?-regulated miRNA network acted as upstream regulators of this oscillatory expression of ?Np63 during cancer progression. This work sheds light on the pleiotropic roles of ?Np63 in cancer and unveils critical functions of TGF? in the metastatic process. SIGNIFICANCE: This study unveils TGF? signaling and a network of four miRNAs as upstream regulators of ?Np63, providing key information for the development of therapeutic strategies to treat cancers that commonly overexpress ?Np63.

SUBMITTER: Bui NHB 

PROVIDER: S-EPMC7385751 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature