Using insertional mutagenesis to identify breast cancer drivers and therapy resistance genes in mice = Insertie mutagenese voor het identificeren van genen betrokken bij de ontwikkeling van borsttumoren en therapie resistentie in muizen

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Using insertional mutagenesis to identify breast cancer drivers and therapy resistance genes in mice = Insertie mutagenese voor het identificeren van genen betrokken bij de ontwikkeling van borsttumoren en therapie resistentie in muizen

Type: Doctoral Thesis
Title: Using insertional mutagenesis to identify breast cancer drivers and therapy resistance genes in mice = Insertie mutagenese voor het identificeren van genen betrokken bij de ontwikkeling van borsttumoren en therapie resistentie in muizen
Author: Kas, S.M.
Issue Date: 2018-11-14
Keywords: In vivo insertional mutagenesis
CRISPR/Cas9
Mouse models of breast cancer
Invasive lobular carcinoma
Somatic gene editing
Fibroblast growth factor receptor
Drug resistance
IM-Fusion
Abstract: In this thesis, we used genetically engineered mouse models to identify genes and pathways that are involved in ILC formation and in the development of resistance to FGFR-targeted therapy. These mice carry conditional alleles of Cdh1, which result in the inactivation of the cell-adhesion molecule E-cadherin when Cre-recombinase is expressed. As mice with mammary-specific inactivation of E-cadherin alone were not prone to develop mammary tumors, they were used to investigate the contribution of additional genetic mutations to the development of ILCs using different genetic approaches. Firstly, we used non-germline modeling to study the role of PI3K-AKT signaling in the development of ILCs by performing intraductal injections of high-titer lentiviruses. Secondly, we employed a Sleeping Beauty (SB)-based insertional mutagenesis screen in conditional Cdh1 knockout mice to identify novel genes and pathways involved in the development of ILCs. We show that active transposon mutagenesis drives ILC formation and analysis of common insertion sites in SB-induced tumors identified a mutually exclusive group of four genes, of which three are frequently aberrated in human ILCs. Lastly, we used active mobilization of transposons in transplanted mouse ILCs to identify genes involved in acquiring resistance to the FGFR inhibitor AZD4547.
Promotor: Supervisor: Jonkers J.
Faculty: Faculty of Science
University: Leiden University
Uri: urn:isbn:9789493014848
Handle: http://hdl.handle.net/1887/66879
 

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