ABSTRACT
Breast 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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: R.P.R., D.D., N.P.; Methodology: S.-H.K., R.P.R., N.P.; Validation: R.P.R., N.P.; Formal analysis: R.P.R., L.H.C., D.D., N.P.; Investigation: S.-H.K., R.P.R., L.H.C., X.L., A.C.B.M.M., D.D., N.P.; Resources: A.J.L., R.C.R., D.P.F., R.L.A.; Data curation: R.P.R.; Writing - original draft: R.P.R., D.D., N.P.; Writing - review & editing: S.-H.K., R.P.R., L.H.C., X.L., A.J.L., R.C.R., D.P.F., A.C.B.M.M., R.L.A., D.D., N.P.; Supervision: D.P.F., D.D., N.P.; Project administration: D.D., N.P.; Funding acquisition: R.L.A., N.P.
Funding
This work was supported by the National Health and Medical Research Council (566871; 1117017 to D.P.F.), the National Breast Cancer Foundation (IN-16-036 to N.P.; Career Fellowship to R.L.A.), the Peter MacCallum Cancer Centre (to R.L.A. and N.P.), Australian Research Council (CE140100011 to D.P.F.) and Cancer Council Victoria (postgraduate scholarship to S.-H.K.). The Olivia Newton-John Cancer Research Institute acknowledges the support of the Operational Infrastructure Program of Victorian Government.
Data availability
The raw microarray signal (CEL) and associated files have been deposited in NCBI's Gene Expression Omnibus (GEO; Edgar et al., 2002) and are accessible through GEO Series accession number GSE111489 (https://www.ncbi.nlm.nih.gov/geo/).
Supplementary information
Supplementary information available online at http://dmm.biologists.org/lookup/doi/10.1242/dmm.034850.supplemental
- Received April 6, 2018.
- Accepted May 15, 2018.
- © 2018. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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