Abstract
ABSTRACTBreast cancer brain metastases remain largely incurable. Although 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 immunocompromised 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. As seen 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.This article has an associated First Person interview with Soo-Hyun Kim, joint first author of the paper.
Highlights
Metastasis accounts for the majority of breast-cancer-related mortalities and approximately 40,000 women were expected to die from the disease in 2017 in the United States alone (Ghoncheh et al, 2016)
The cells were subjected to four rounds of in vivo enrichment by inoculation of cells in the mammary gland of BALB/c mice, followed by explant cultures of excised brain lesions, fluorescence-activated cell sorting (FACS) and in vitro expansion of mCherry-positive cells to generate the 4T1Br4 line
To prioritise potential therapeutic targets driving brain-specific metastasis, we identified 11 consensus genes contributing to enrichment in this 80-gene pathway across all brain-metastatic 4T1Br4 and GSE12276 tumours, two of which met the differential expression threshold [fold change (FC)≥1.5, P≤0.05] to qualify as members of the BrCa BSM gene set: FCER1G and PECAM1 (Table 2)
Summary
Metastasis accounts for the majority of breast-cancer-related mortalities and approximately 40,000 women were expected to die from the disease in 2017 in the United States alone (Ghoncheh et al, 2016). The incidence of brain metastasis in breast cancer patients is estimated at ∼30% and is rising, despite more effective systemic therapies (Tabouret et al, 2012). Therapeutic options consist primarily of surgery, whole brain radiation therapy (WBRT), stereotactic radiosurgery and chemotherapy, but these approaches, while extending life, are rarely curative (Eichler et al, 2011). Cognitive impairment due to damage to the surrounding normal tissue limits the dose and therapeutic efficacy of radiation therapy (Lee et al, 2012; McTyre et al, 2013). The efficacy of chemotherapy against brain metastases is limited by the poor penetration of most chemotherapeutic drugs through the blood-brain barrier (BBB) and/or by the acquisition of resistance once brain metastases are established (Arslan et al, 2014; Lockman et al, 2010)
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