Abstract B14: Gain of function contribution of mutant AKT-E17K to lung and mammary tumorigenesis in mouse models

Abstract

Abstract The hotspot Akt1-E17K mutation that results in a glutamic acid to lysine substitution in the seventeenth amino acid position in the pleckstrin homology domain of Akt1 occurs in approximately 0.6-2% of human lung cancers and in 6-8% of human breast cancer. To determine whether this Akt1 variant is a bona-fide activating mutation and to investigate the mechanistic basis of the Akt1 gain of function dependent mechanisms in lung and breast tumorigenesis we generated a transgenic Cre-inducible murine strain in the ROSA26 (R26) locus (R26-Akt1-E17K mice). To analyse the effects of mutant Akt1 in lung epithelium, we made use of two different systems to activate the transgene into pulmonary cells: intranasal instillation of an Adenovirus carrying the Cre recombinase (Ad-Cre) and the mating of R26-Akt1-E17K mice with Thyroid transcription factor-1 (TTF-1)-Cre mice that allow expression of the transgenes in lung epithelium. We report that in murine lung epithelium, mutant Akt1-E17K induces bronchial and/or bronchiolar hyperplastic lesions that at low frequency progress to frank carcinoma and accelerates tumor formation induced by chemical carcinogens. To assess the potential role of Akt1 as an oncogene in mammary epithelium, we examined the consequences of the mutant Akt1-E17K in the mammary gland of mice by mating of R26-Akt1-E17K mice with Mouse mammary tumor virus (MMTV)-Cre mice. We provide strong evidences that the expression of mutant Akt1-E17K in the mammary gland, driven by the MMTV promoter, was sufficient to produce a tumoral response in mice starting from 5-6 months of age. Transgenic mice developed invasive and in situ carcinoma in 45% of the cases and, in agreement with these results, mice that express activated Akt1 in the mammary gland showed poor survival Citation Format: Donatella Malanga, Stefania Belmonte, Stefania Belmonte, Carmela De Marco, Orlando Paciello, Alfonso Baldi, Giuseppe Viglietto. Gain of function contribution of mutant AKT-E17K to lung and mammary tumorigenesis in mouse models. [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 B14.