Enhanced susceptibility to chemical induction of ovarian tumors in mice with a germ line p53 mutation.
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.
Wang
Yian
Y
Department of Surgery, The Washington University School of Medicine, St Louis, MO 63110, USA.
Zhang
Zhongqiu
Z
Lu
Yan
Y
Yao
Ruisheng
R
Jia
Dongmei
D
Wen
Weidong
W
LaRegina
Marie
M
Crist
Keith
K
Lubet
Ronald
R
You
Ming
M
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene