Abstract 249: A Sleeping Beauty screen in mice identifies Zmiz1 as a candidate cancer gene in human squamous cell carcinomas

Abstract

Abstract Cutaneous squamous cell carcinoma (SCC) is the second most frequent cancer in the United States, with over 250,000 new cases diagnosed annually. Current treatments rely upon surgical excision of the cancerous tissue. Often, however, surgical removal can be difficult for patients because tumors commonly develop on sun-exposed surfaces such as the face, ears, and hands. In addition, a low percentage of patients exhibit aggressive metastases that are not easily removed and often result in death. A deeper understanding of the underlying genes involved in disease initiation and progression will be essential for the development of nonsurgical treatments. A recent Sleeping Beauty (SB) transposon insertional mutagenesis screen identified Zmiz1 as a candidate cancer gene in cutaneous SCCs. Intriguingly, over 90% of SB-induced skin SCCs harbored mutations within the Zmiz1 gene, predicted to cause overexpression of an N-terminally truncated protein, which we named Zmiz1mut. Immunohistochemistry (IHC) analysis of SB-induced SCCs revealed aberrant nuclear Zmiz1 localization in tumor samples, while nuclear staining was absent in normal mouse skin. Importantly, nuclear Zmiz1 was also detected in ∼70% of human SCC tumors analyzed by IHC, indicating that aberrant Zmiz1 expression may also play a role in human disease. Furthermore, we have discovered that Zmiz1 nuclear staining is present in a significant percentage of breast, colon, and ovarian cancers. The purpose of this study is to determine the functional significance of Zmiz1 mutation in cutaneous SCC. To this end, we engineered transgenic mice that express Zmiz1mut in a Cre-dependent manner. We crossed these mice to a K14-Cre strain to induce Zmiz1mut expression in the skin. Offspring inheriting both alleles proved to be tumor-prone, with over 80% of these animals developing SCC. These data confirm that Zmiz1 has oncogenic potential in the skin. Sequencing analysis of cDNA from tumors produced by our Zmiz1mut transgenic model uncovered no mutations in either p53 or H-Ras_mutations that are observed in other mouse models of skin cancer. IHC was also performed on tumor sections. As before, we observed a strong nuclear staining pattern in the tumors induced by Zmiz1mut expression, leading us to hypothesize that nuclear accumulation of Zmiz1 plays an active role in tumorigenesis. Current efforts are focused on further characterization of our unique skin cancer model and discovering the driving force behind nuclear accumulation of Zmiz1. 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 249.