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TP63 is required to maintain stem cell pluripotency and suppresses the metastatic potential of cancer cells through multiple mechanisms. These functions are differentially regulated by individual isoforms, necessitating a deeper understanding of how the distinct transcriptional programs controlled by these isoforms affect cancer progression and outcomes. In this study, we conducted a pan-cancer analysis of The Cancer Genome Atlas to identify transcriptional networks regulated by TAp63 and ΔNp63 using transcriptomes derived from epidermal cells of TAp63 -/- and ΔNp63 -/- mice. Analysis of 17 cancer developmental and 27 cancer progression signatures revealed a consistent tumor suppressive pattern for TAp63. In contrast, we identified pleiotropic roles for ΔNp63 in tumor development and found that its regulation of Lef1 was crucial for its oncogenic role. ΔNp63 performed a distinctive role as suppressor of tumor progression by cooperating with TAp63 to modulate key biological pathways, principally cell-cycle regulation, extracellular matrix remodeling, epithelial-to-mesenchymal transition, and the enrichment of pluripotent stem cells. Importantly, these TAp63 and ΔNp63 signatures prognosticated progression and survival, even within specific stages, in bladder and renal carcinomas as well as low-grade gliomas. These data describe a novel approach for understanding transcriptional activities of TP63 isoforms across a large number of cancer types, potentially enabling identification of patient subsets most likely to benefit from therapies predicated on manipulating specific TP63 isoforms. Significance: Transcriptomic analyses of patient samples and murine knockout models highlight the prognostic role of several critical mechanisms of tumor suppression that are regulated by TP63. Cancer Res; 78(2); 451-62. ©2017 AACR .

Distinct TP63 Isoform-Driven Transcriptional Signatures Predict Tumor Progression and Clinical Outcomes