AKT1E¹⁷K Is Oncogenic in Mouse Lung and Cooperates with Chemical Carcinogens in Inducing Lung Cancer.

Donatella Malanga,Orlando Paciello,Caterina Camastra,Duarte Mendes Oliveira,Stefania Belmonte,Fabiana Colelli,Teresa Mirante,Chiara Mignogna,Marzia Scarfò,Carmela De Marco,Monica Gagliardi,Giuseppe Viglietto,Henrik Fagman,Serenella Papparella,Antonia Rizzuto

doi:10.1371/journal.pone.0147334

Abstract

The hotspot AKT1E17K mutation in the pleckstrin homology domain of AKT1 occurs in approximately 0.6–2% of human lung cancers. Recently, we have demonstrated that AKT1E17K transforms immortalized human bronchial cells. Here by use of a transgenic Cre-inducible murine strain in the wild type Rosa26 (R26) locus (R26-AKT1E17K mice) we demonstrate that AKT1E17K is a bona-fide oncogene and plays a role in the development of lung cancer in vivo. In fact, we report that mutant AKT1E17K induces bronchial and/or bronchiolar hyperplastic lesions in murine lung epithelium, which progress to frank carcinoma at very low frequency, and accelerates tumor formation induced by chemical carcinogens. In conclusion, AKT1E17K induces hyperplasia of mouse lung epithelium in vivo and cooperates with urethane to induce the fully malignant phenotype.

Highlights

Lung cancer is a leading cause of cancer-related deaths, being associated with a 5-year worldwide survival rate of less than 15% [1,2]
To further characterise the lesions detected in transgenic R26-AKT1E17K mice, we evaluated lung hyperplasia by analysing the number of epithelial layers in the bronchial epithelium and the percentage of hyperplasia on the whole area of 3 serial sections derived from representative R26-AKT1E17K mice after 6 (n = 3) and 9 (n = 3) months from Adenoviruses expressing Cre (Ad-Cre) administration
It is of note that after 18 months from the treatment, two out of seven R26-AKT1+/E17K mice treated with Ad-Cre developed a single nodule each, which was diagnosed as bronchio-alveolar adenocarcinoma with papillary pattern consisting of cords and nests of epithelial cells surrounded by sparse fibrovascular stroma (Fig 3D)

Summary

Introduction

Lung cancer is a leading cause of cancer-related deaths, being associated with a 5-year worldwide survival rate of less than 15% [1,2]. Mutational activation of the epidermal growth factor receptor (EGFR) pathway is the major pathogenic event in non tobacco-induced adenocarcinoma (ADC), whereas the pathway driven by v-Ki-ras2/Kirsten rat sarcoma viral oncogene homolog (KRAS) is involved in tobacco-mediated lung carcinogenesis [3,4,5,6]. Activating mutations in EGFR are typically not present in lung squamous cell carcinoma (SCC), the second most common type of NSCLC [7], and targeted therapy is ineffective. Recent studies showing 2–4% rate of p110 α-catalytic subunit of PI3K (PIK3CA) mutations [8,9,10] and 1% rate of AKT1 mutations [11,12] in SCC have suggested that targeting these genes may prove a successful therapeutic option [7,13,14,15].

Methods

Results

Conclusion