Abstract A16: Defining the essential in vivo oncogenic function of p63 in squamous cell carcinoma.

Abstract

Abstract The p63 transcription factor controls diverse functional programs within the epithelium. Despite its essential developmental role, however, the precise contribution of p63 in cancer remains controversial, and the relevant p63-dependent pathways remain poorly understood. Squamous Cell Carcinoma (SCC) is a common and treatment-refractory form of human cancer that can arise in various epithelial tissues including the lungs, skin, and head and neck region. In SCC, the p63 locus is frequently targeted for genomic amplification and/or overexpression, leading to tumor-specific up-regulation of ΔNp63α. In vitro studies point to a role for ΔNp63α in survival of SCC cells, yet such models are unlikely to fully reflect the contribution of p63 in squamous cancers. We therefore developed an in vivo model in order to address in a definitive manner the role of p63 in progression and maintenance of this disease. We generated a murine model of SCC that faithfully recapitulates the molecular and pathological features of human SCC, including high-level expression of p63, invasion and metastasis. We crossed this model to a conditional p63-null allele (p63flox) and a tamoxifen-inducible Cre transgene, K14-CreER. Remarkably, we find that genetic excision of endogenous p63 in SCC-bearing mice results in rapid, dramatic, and sustained regression of tumors. This effect is due in large part to increased tumor-specific apoptosis, and is associated with no appreciable effects on normal p63-expressing tissues. We then performed global gene expression profiling and extensive validation in order to uncover the key transcriptional programs mediating this survival effect. Unlike previous in vitro work which defined a predominant role for pro-apoptotic Bcl-2 family members in p63-dependent tumor cell survival, our in vivo studies have uncovered a key role for growth factor receptor tyrosine kinases (RTKs) downstream of p63. We find that p63 is a direct transcriptional regulator of these RTK genes, and we support the relevance of these findings to human disease by showing a strong correlation between p63 and these essential p63-regulated genes in human head and neck SCC tumors. Collectively, these studies have established the oncogenic function of p63 in SCC, and they have uncovered a novel and essential pathway mediating p63-dependent tumor maintenance. Ongoing work to be presented seeks to validate this RTK pathway as a potentially important therapeutic target in SCCs which overexpress p63. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A16.