Colelli, Fabiana (2014) Conditional activation of AKT1E17K promotes breast tumorigenesis in a knock-in mouse model. [Tesi di dottorato]

tesi dottorato Fabiana Colelli XXVI ciclo.pdf

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Item Type: Tesi di dottorato
Resource language: English
Title: Conditional activation of AKT1E17K promotes breast tumorigenesis in a knock-in mouse model
Date: 28 March 2014
Number of Pages: 74
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Veterinaria e Produzioni Animali
Scuola di dottorato: Scienze veterinarie per la produzione e la sanità
Dottorato: Organismi modello nella ricerca biomedica e veterinaria
Ciclo di dottorato: 26
Coordinatore del Corso di dottorato:
De Girolamo,
Viglietto, GiuseppeUNSPECIFIED
Date: 28 March 2014
Number of Pages: 74
Keywords: breast cancer, AKT1E17K, mouse model
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/18 - Genetica
Area 06 - Scienze mediche > MED/06 - Oncologia medica
Aree tematiche (7° programma Quadro): SALUTE e TUTELA DEL CONSUMATORE > Biotecnologie, strumenti e tecnologie generiche per la salute umana
Date Deposited: 10 Apr 2014 08:59
Last Modified: 22 Jan 2015 12:03

Collection description

Activating mutations in the PI3K/AKT pathway are present in majority of breast cancer. The gain of function mutation E17K of AKT1, was found in 8% of breast cancers, especially ductal carcinomas, but several studies performed so far have failed to define the real role of this mutation in the breast tissue trnsformation. To investigate the role of the AKT1E17K in breast tumorigenesis, we explored the phenotype of a new mouse model which express the mutant transgene in mammary epithelium. The expression of AKT1E17K enhances the activity of the kinase and the phosphorilation status of downstream substrates, such as FOXO1 and GSK3α/β. In addition, transgenic mice showed an increased cellularity 8-10 times higher than control mice breast tissues. Moreover 70% of transgenic mice expressing the mutant form of AKT1 develop ductal carcinomas from medium to high grade. We have identified also the contribution of AKT1E17K in the generation and maintenance of putative breast cancer stem cells. Finally, using a pharmacological study, we were able to slow down tumor formation by inhibiting downstream effect of AKT1 pathway. All together these data have allowed us to demonstrate that AKT1E17K is itself capable to induct the onset of ductal carcinoma in transgenic mice.


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