Invasive lobular carcinoma (ILC) is the second most common type of breast cancer. Hallmarks of ILC include disruption of adherens junctions and hyperactivation of phosphoinositide 3-kinase (PI3K)... Show moreInvasive lobular carcinoma (ILC) is the second most common type of breast cancer. Hallmarks of ILC include disruption of adherens junctions and hyperactivation of phosphoinositide 3-kinase (PI3K)-mTOR signaling. The tumor suppressor PTEN regulates PI3K signaling. We present a preclinical mouse model of ILC metastasis, based on inactivation of the adherens junction protein E-cadherin and the tumor suppressor p53 and surgical excision of primary tumors. In this model, pharmacological mTOR inhibition blocks growth of primary tumors as well as metastatic disease, and this response is partially dependent on the adaptive immune system. Loss of E-cadherin mouse mammary epithelium leads to apoptosis, and PTEN activation alone results in squamous metaplastic mammary tumors, but a combination of these events leads to ILC formation, indicating a causal role of PI3K signaling together with E-cadherin loss in ILC. Combined somatic loss of the adherens junction molecule p120 and p53 in the mouse mammary gland leads to metaplastic mammary tumors, and loss of p120 in breast cancer cell lines promotes anoikis resistance through hypersensitization of growth factor receptor (GFR) signaling. Combined inactivation of E-cadherin, p120 and p53 induces basal-like tumors, with an epithelial-to- mesenchymal-transition (EMT) phenotype, and no ILC formation. Show less
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
