Abstract A34: Mammary-specific, doxycycline-regulated transposon mobilization for identifying driver genes in mouse models of breast cancer

Abstract

Abstract Transposon-mediated mutagenesis offers a powerful tool for discovering genetic changes that contribute to cancer pathogenesis. Tissue-specific transposon mobilization has been exploited widely to identify candidate cancer genes in a variety of tissues, including intestine, pancreas, and liver. These models typically use tissue-specific expression of the Cre recombinase to activate a latent transposase allele, which in turn mobilizes a mutagenic transposon. Notably, transposase expression cannot be halted once activated in these models, potentially leading to unwanted transposition events that either delete driver insertions or create additional passenger insertions. As an alternative strategy, we generated transgenic mice harboring the SB11 transposase under the control of tet operator sequences. Tet-O-SB11 founder lines were characterized that permit a range of transgene expression levels when crossed to mice carrying a mammary-specific transactivator, MMTV-rtTA. We show that efficient mobilization of the T2/Onc transposon in mammary tissue requires high-level SB11 expression, which strictly depends on doxycycline administration in our models. Furthermore, efficient T2/Onc mobilization enabled by high-level SB11 expression strongly cooperated with Wnt1 transgene expression to drive mammary tumorigenesis in vivo. Preliminary analysis of transposon integration sites in these mammary tumors confirms that transposon-mediated mutations serve as pathogenic driver events. Temporal regulation of transposase-mediated mutagenesis may offer a flexible tool for discovering driver events operative at various stages of tumor progression. Citation Format: Shelley A. Gestl, Edward J. Gunther. Mammary-specific, doxycycline-regulated transposon mobilization for identifying driver genes in mouse models of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A34.