194 Distinct and redundant pro-proliferative functions of p63 and p73 in cutaneous squamous cell carcinoma

Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Although p53 gene is frequently mutated in human tumors and more specifically in cutaneous squamous cell carcinomas (cSCC), little is known about the other two members of the p53 family, p63 and p73. In this study, we demonstrate that p63 and p73 protein expression is strongly upregulated in a large cohort of pre-malignant actinic keratoses (AK) and in cSCC with different tumor grades, and both proteins play a positive role in sustaining cell proliferation and tumor growth. Global gene expression profiling followed by functional annotation analysis revealed that p63 and p73 coordinately control a large number of genes involved in cell cycle and DNA metabolic processes, while independently regulating a subset of other target genes. Among them, p63 and p73 directly transactivate several ligands of Epidermal Growth Factor Receptor (EGFR), highly expressed in AK and cSCC. Interestingly, in p63-depleted cells, treatment with EGFR ligands is sufficient to restore cell cycle progression. In p73-depleted cells, EGFR ligands can only partially rescue proliferation, whereas knockdown of the p53 family target CDKN1A fully restores cell cycle progression in p73-depleted cells. Intradermal tumorigenicity assays followed by in vivo imaging revealed that loss of p63, p73, or AREG, the most highly secreted EGFR ligand, is sufficient to impair cSCC-derived tumors. Our study indicates that p63 and p73 exert non-overlapping pro-proliferative functions that favor early stages of cSCC formation, and uncover a subset of EGFR ligands as potential drug targets in cSCC.