Abstract 84: Functional evaluation of synchronous inactivation of PTEN and P53 in a murine model of prostate cancer

Abstract

Abstract The prostate-specific PTEN conditional knockout (K/O) mouse model has been extremely useful as tool to investigate the biology of the tumorigenesis process, particularly during early tumor development. However, cancer progression is gradual with a low metastatic rate. This feature poses a challenge to this model when used for survival studies and end-stage biological characterization of prostate cancer. Inactivation of P53 is a characteristic that is frequent in advanced prostate cancer. To address this issue, we generated series of double K/O mice based on either P53 loss or gain of function in combination with PTEN inactivation. Conditional inactivation of both PTEN and P53 results in the development of aggressive tumors compared to PTEN K/O mice. Homozygous PTEN/P53-mutants mice grow prostate tumors at a faster rate and experience dramatically reduced survival. Homozygous double K/O mice also developed a higher frequency and number of metastases. Furthermore, haploinsufficient P53 gain of function mutations contributed to an invasive cancer phenotype compared to P53 loss of function haploinsufficient tumors. In conclusion, our analyses demonstrate that synchronous inactivation of PTEN and P53 promotes an aggressive prostate cancer and provides rationale that supports that use of such models is better suited for studies requiring long-term survival and end-stage cancer characterization. Citation Format: Hirotsugu Uemura, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Marco A. De Velasco. Functional evaluation of synchronous inactivation of PTEN and P53 in a murine model of prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 84. doi:10.1158/1538-7445.AM2014-84