In this thesis, we used genetically engineered mouse models and a variety of cell-culture based assays to identify genes and pathways that are involved in the development and treatment of invasive... Show moreIn this thesis, we used genetically engineered mouse models and a variety of cell-culture based assays to identify genes and pathways that are involved in the development and treatment of invasive lobular carcinoma (ILC). To identify novel genes and pathways involved in the development of ILCs we employed a Sleeping Beauty (SB)-based insertional mutagenesis screen in conditional Cdh1 knockout mice. 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 (MYH9, MYPT1/2 and ASPP2), three of which are frequently altered in human ILCs. We then went on to show that these hits not only drive ILC development but also do so through a shared mechanism. We identified that all four hits result in actomyosin relaxation which enables E-cadherin deficient mammary epithelial cells to invade into the mammary stroma and initiate tumor development. In addition, we show that mammary epithelial cells that lose E-cadherin expression can survive in the fibrous stroma directly surrounding the mammary ducts through interactions with components of the basement membrane. Lastly, we used active mobilization of transposons to identify resistance mechanisms to the FGFR inhibitor AZD4547. Show less
