Abstract 4158: The p53 gain-of-function mutation p53R172H promotes oral cancer progression in response to DNA damage

Abstract

Abstract Oral cancer is one of the most common cancers worldwide, presenting high mortality rates and a severe impact on the quality of life of patients and survivors. Oral cancers arise from the accumulation of genetic alterations. Some of the most prevalent mutations found in patients with oral cancer involve mutations in Ras and p53 genes, although the mutation rates exhibit geographical variation, most likely as a result of different exposure to carcinogens. Most p53 mutations result in the expression of mutant forms of p53, rather than inactivation of the p53 gene. To determine the role of these mutations during oral cancer development we generated mice in which the endogenous K-rasG12D allele and p53 gain-of-function mutation p53R172H could be activated exclusively in the oral epithelium. We found that the p53R172H mutation, but not deletion of p53, cooperates with K-rasG12D to initiate oral tumor formation, accelerates oral tumor growth and promotes progression to squamous cell carcinoma. Expression profiling of the tumors that developed in these mice revealed that cyclin B1 was overexpressed in the oral tumors that expressed p53R172H compared to tumors with no p53. To expand the functional studies, we generated cell lines from these mouse oral tumors. Similar to the primary tumors, cell lines derived from the tumors expressing p53R172H generated tumors that grew faster upon injection in nude mice than cell lines that lacked p53. Using these cell lines we found that the expression of cyclin B1 was dramatically induced in the p53R172H cells in response to DNA damage, suggesting that cyclin B1 may contribute to the oncogenic properties p53R172H in oral tumor cells in response to DNA damage. Notably, we observed DNA damage in the oral tumors, as determined by staining for γ-H2AX. Since these tumors were initiated by oncogenic K-ras, we speculated that oncogene activation induced DNA damage in the tumors, thereby allowing the induction of cyclin B1 expression. Consistent with this hypothesis we found that suppressing K-ras in cells that express p53R172H resulted in significant reduction in cyclin B1 expression, indicating that p53R172H can induce the expression of cyclin B1 in response to oncogenic K-ras. In addition, we found increased DNA damage in the oral tumors that expressed p53R172H compared to tumors that lack p53, suggesting that p53R172H may modulate the DNA damage response. Together, these findings indicate that p53R172H may promote oral tumor progression in response to DNA damage, and suggest that attenuation of the DNA damage response may contribute to the oncogenic properties of mutant p53. 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 4158.