Mutations in the p53 tumor suppressor gene are found in about half of the squamous cell carcinomas (SCC) that arise in the skin and oral cavity. Most of these mutations are missense mutations that result in the expression of altered forms of p53, some of which acquire oncogenic properties. We previously showed that the p53 gain-of-function mutation p53R172H cooperates with Ras activation during skin cancer initiation, progression to carcinoma and metastasis. However, it is unclear whether p53 gain- and loss-of-function mutations predispose differently to SCC formation when activated in the absence of additional oncogenic mutations. To address this question we generated mice in which deletion of p53 (loss-of-function) or activation of the p53R172H mutation (gain-of-function) were induced in mouse stratified epithelia. We found that over 70% of the mice developed skin or oral SCCs, with similar kinetics for mice with p53 gain- or loss-of-function mutations, suggesting that in the absence of Ras mutations the oncogenic role of p53R172H in SCC initiation is minimized. To identify mechanisms leading to SCC development in these mice we analyzed the status of pathways that are frequently involved in human SCCs. We observed that Erk1/2 activation was blocked in most of the SCCs. Consistently, oncogenic mutations in Ras genes were only found in <5% of the SCC analyzed. Notably, we found overexpression of cyclin D1 and activation of Akt in over 50% of the SCCs, suggesting an important contribution for these oncogenic alterations in SCC development in these mice. Importantly, p16INK4a and p19ARF were overexpressed in most of the SCCs, suggesting that in the absence of p53, alternative tumor suppressor mechanisms are activated to prevent tumor progression. To determine whether p53 mutations and p16/p19 cooperate in SCC formation we generated mice in which p53 mutations and deletion of the Ink4a/Arf locus were induced in the epidermis. These mice developed skin carcinomas significantly faster than mice with mutations in p53 only. In addition, in the presence of the Ink4a/Arf deletion, the p53R172H mutation induced accelerated SCC formation compared to deletion of p53, again suggesting that the oncogenic properties of mutant p53 are exposed in the presence of additional genetic alterations. The tumors that developed in these mice were classified as spindle cell carcinomas (SPCC) and generated metastasis in over 60% of the mice. Ongoing experiments are underway to identify molecular mechanisms involved in the generation of SPCCs and metastasis in this model.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 479.