Enhanced Susceptibility to Chemical Induction of Ovarian Tumors in Mice with a Germ Line p53 Mutation Yian Wang, 1 Zhongqiu Zhang, 1 Yan Lu, 1 Ruisheng Yao, 1 Dongmei Jia, 1 Weidong Wen, 1 Marie LaRegina, 2 Keith Crist, 3 Ronald Lubet, 4 and Ming You 1 1 Department of Surgery and 2 Division of Comparative Medicine, Washington University School of Medicine, St. Louis, Missouri; 3 Medical College of Ohio, Toledo, Ohio; and 4 Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland Abstract Mice with a germ line p53 mutation (p53 Ala135Val/wt ) display increased susceptibility to lung, skin, and colon carcinogenesis. Here, we show that p53 Ala135Val/wt mice developed ovarian tumors significantly more rapidly than their wild-type littermates after 7,12-dimethylbenz(a )anthracene (DMBA) treatment. Approximately 50% of the ovarian tumors in p53 wt/wt mice and 23% in p53 Ala135Val/wt mice are adenocarcinomas and the remaining tumors were adenocarcinoma mixed with sarcoma or ovarian sarcomas. All of the p53 Ala135Val/wt mice had died of ovarian tumors 25 weeks after the initial DMBA treatment, whereas >50% of p53 wt/wt mice were still alive. These mice not only have a shortened tumor latency but also closely resemble a subset of human ovarian tumors containing the p53 mutation. Microarray and GenMAPP analyses revealed that the mutant p53 (Ala135Val) affected several cellular processes, including the cell cycle, apoptosis, and Wnt pathways. These findings indicate that a germ line p53 mutation significantly enhanced DMBA-induced ovarian tumor development and progression. (Mol Cancer Res 2008;6(1):99–109) Introduction Ovarian cancer is the fifth leading cause of cancer death in women, and is the leading cause of death from gynecologic malignancy. It has been estimated that there were 20,180 new cases and 15,310 ovary cancer deaths in the United States during 2006 (1). Ovarian cancer is classified into three major groups based on their distinct histologic origins. The most common ovarian cancers are epithelial cancers, which originate from the ovarian surface lining. This type accounts for f90% of all ovarian cancers. The second type of ovarian cancers are germ cell tumors, which account for f5% of all ovarian cancers. The third type of ovarian cancers are the specialized stromal cell cancers. Although it accounts for only <5% of all ovarian cancers, it is a highly aggressive form of cancer. Ovarian cancer is idiopathic, although it is associated with multiple genetic alterations. Dysfunction of p53 is one of the most common genetic alterations found in cancer, occurring in up to 50% of all human malignancies (2). The p53 tumor suppressor protein is a central regulator of cell growth, DNA damage repair, and apoptosis (3). It directly activates the expression of a substantial number of genes important for cell cycle regulation and apoptosis (4). Although, p53 gene alterations are rare events in benign ovarian tumors, previous studies have shown that p53 is mutated in f50% of late stage (stage III/IV) ovarian cancers (5). Furthermore, mutated p53 genes with resultant overexpression of p53 proteins occurs frequently in ovarian sarcomas (6). We reported that p53 Ala135Val/wt mice are highly susceptible to carcinogen-induced tumors including lung (7) and skin tumors (8). However, the role of germ line p53 mutation in mouse ovarian carcinogenesis has not been examined previ- ously in this rodent model. For this reason, we have carried out an ovarian carcinogenesis study with 7,12-dimethylben- z(a )anthracene (DMBA). Here, we report that p53 Ala135Val/wt mice display significantly increased susceptibility to DMBA- induced ovarian tumor carcinogenesis. Alterations of several cellular processes, including cell cycle arrest, apoptosis, and Wnt pathways, may mediate enhanced DMBA-induced ovarian tumor carcinogenesis in p53 Ala135Val/wt mice. Results and Discussion Three months post-DMBA treatment, p53 Ala135Val/wt mice had developed significantly more advanced tumor phenotypes (larger ovarian tumors) compared with their wild-type litter- mates. The survival rate of p53 wt/wt mice was significantly higher than p53 Ala135Val/wt mice (Fig. 1). Most of the p53 Ala135Val/wt mice were dead or moribund before the end of the experiment due to advanced ovarian tumors. On an average of 17 weeks post-DMBA treatment, 100% of the p53 Ala135Val/wt mice (40 of 40) had developed tumors. Whereas in the p53 wt/wt group, 40 weeks posttreatment, >80% (28 of 35) of the mice had developed tumors. No mice were found dead or sick in Received 5/10/07; revised 8/28/07; accepted 9/4/07. Grant support: National Cancer Institute, NIH (R01CA113793 and N01CN43308). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Requests for reprints: Ming You, Department of Surgery, The Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: 314-462-9294; Fax: 314-362-9366. E-mail: youm@msnotes.wustl.edu Copyright D 2008 American Association for Cancer Research. doi:10.1158/1541-7786.MCR-07-0216 Mol Cancer Res 2008;6(1). January 2008 99 Research. on December 3, 2015. © 2008 American Association for Cancer mcr.aacrjournals.org Downloaded from