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Title: Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis.
Austin Authors: Kim, Soo-Hyun;Redvers, Richard P;Chi, Lap Hing;Ling, Xiawei;Lucke, Andrew J;Reid, Robert C;Fairlie, David P;Baptista Moreno Martin, Ana Carolina;Anderson, Robin L ;Denoyer, Delphine;Pouliot, Normand
Affiliation: Metastasis Research Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
Metastasis Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Division of Chemistry and Structural Biology, ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Qld, Australia
Department of Gerontology, Federal University of São Carlos, São Carlos, SP, Brazil
Department of Pathology, The University of Melbourne, Victoria, Australia
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia
Matrix Microenvironment & Metastasis Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Issue Date: 21-May-2018
Date: 2018-05-21
Publication information: Disease models & mechanisms 2018; online first: 21 May
Abstract: Breast cancer brain metastasis remains largely incurable. While several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immune-compromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain-selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo and potent radio-sensitising properties in vitro The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis.
DOI: 10.1242/dmm.034850
ORCID: 0000-0002-7039-8638
Journal: Disease models & mechanisms
PubMed URL: 29784888
Type: Journal Article
Subjects: 4T1Br4
Brain metastasis
Breast cancer
Histone deacetylase inhibitor
Syngeneic mouse model
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