Loss of TAp63 limits epithelial tumour initiation through enhanced p53 activity

The p53 family of transcription factors is central to epithelial homeostasis, tumour suppression, and stress responses. Whilst the other family member TAp63 is clearly linked to tumour-suppressive activities, the underlying molecular events in early tumorigenesis and in particular its interplay with p53 remains partially unclear. Using the two-stage DMBA/TPA skin carcinogenesis model in TAp63-deficient mice, we unexpectedly found that loss of TAp63 markedly reduces tumour initiation and progression. TAp63 deficiency impairs the ability of epidermal cells to mount effective stress responses and sustain cellular programs required for tumour development, with associated changes in DNA damage responses, apoptotic signalling, and global pathways. Mechanistically, loss of TAp63 enhances expression of wild-type p53, suggesting that disruption of p53 family balance reshapes cellular responses to oncogenic stress. Elevated p53 activity in TAp63-null epidermis correlates with a tumour-suppressive environment that limits initiation. These findings reveal an unexpected pro‑tumorigenic role for TAp63 in epithelial carcinogenesis and identify p53 family network balance as a key determinant of tumour development, providing a framework to reconcile dual roles of TAp63 in cancer and highlighting the importance of transcriptional network dynamics in tumour susceptibility.