PT - JOURNAL ARTICLE AU - Soo-Hyun Kim AU - Richard P. Redvers AU - Lap Hing Chi AU - Xiawei Ling AU - Andrew J. Lucke AU - Robert C. Reid AU - David P. Fairlie AU - Ana Carolina Baptista Moreno Martin AU - Robin L. Anderson AU - Delphine Denoyer AU - Normand Pouliot TI - Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis AID - 10.1101/296384 DP - 2018 Jan 01 TA - bioRxiv PG - 296384 4099 - http://biorxiv.org/content/early/2018/04/06/296384.short 4100 - http://biorxiv.org/content/early/2018/04/06/296384.full AB - 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.SUMMARY STATEMENT We introduce a new syngeneic mouse model of spontaneous breast cancer brain metastasis, demonstrate its phenotypic, functional and transcriptomic relevance to human TNBC brain metastasis and test novel therapies.AbbreviationsBBBBlood-brain barrierBCMBrain conditioned mediumBrCa BSMBreast Cancer Brain-Specific MetastasisCTCCirculating tumour cellDAPI,4′,6-diamidino-2-phenylindoleEROestrogen receptorFBSfoetal bovine serumFACSfluorescence-activated cell sortingGFAPGlial fibrillary acidic proteinH&EHematoxylin and eosinHDACiHistone deacetylase inhibitorHER2Human epidermal growth factor receptor 2PBSPhosphate-buffered salinePRProgesterone receptorRTBRelative tumour burdenSFMSerum-free mediumSRBSulforhodamine BTNBCTriple Negative Breast cancer