Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis
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 poo...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2018-07-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/11/7/DMM034850 |
| _version_ | 1818468637644685312 |
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| author | Soo-Hyun Kim Richard P. Redvers Lap Hing Chi Xiawei Ling Andrew J. Lucke Robert C. Reid David P. Fairlie Ana Carolina Baptista Moreno Martin Robin L. Anderson Delphine Denoyer Normand Pouliot |
| author_facet | Soo-Hyun Kim Richard P. Redvers Lap Hing Chi Xiawei Ling Andrew J. Lucke Robert C. Reid David P. Fairlie Ana Carolina Baptista Moreno Martin Robin L. Anderson Delphine Denoyer Normand Pouliot |
| author_sort | Soo-Hyun Kim |
| collection | DOAJ |
| description | 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. This article has an associated First Person interview with Soo-Hyun Kim, joint first author of the paper. |
| first_indexed | 2024-04-13T21:13:59Z |
| format | Article |
| id | doaj.art-799356fe301541b5aff255c344d8d69e |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-13T21:13:59Z |
| publishDate | 2018-07-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-799356fe301541b5aff255c344d8d69e2022-12-22T02:29:45ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112018-07-0111710.1242/dmm.034850034850Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasisSoo-Hyun Kim0Richard P. Redvers1Lap Hing Chi2Xiawei Ling3Andrew J. Lucke4Robert C. Reid5David P. Fairlie6Ana Carolina Baptista Moreno Martin7Robin L. Anderson8Delphine Denoyer9Normand Pouliot10 Metastasis Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia Metastasis Research Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia Metastasis Research Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia Metastasis Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, 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, 4072, 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, 4072, 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, 4072, Australia Department of Gerontology, Federal University of São Carlos, São Carlos, SP, 13565-905, Brazil Metastasis Research Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia Matrix Microenvironment & Metastasis Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia School of Cancer Medicine, La Trobe University Bundoora, VIC, 3086, Australia 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. This article has an associated First Person interview with Soo-Hyun Kim, joint first author of the paper.http://dmm.biologists.org/content/11/7/DMM0348504T1Br4Breast cancerBrain metastasisSyngeneic mouse modelHistone deacetylase inhibitor |
| spellingShingle | Soo-Hyun Kim Richard P. Redvers Lap Hing Chi Xiawei Ling Andrew J. Lucke Robert C. Reid David P. Fairlie Ana Carolina Baptista Moreno Martin Robin L. Anderson Delphine Denoyer Normand Pouliot Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis Disease Models & Mechanisms 4T1Br4 Breast cancer Brain metastasis Syngeneic mouse model Histone deacetylase inhibitor |
| title | Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis |
| title_full | Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis |
| title_fullStr | Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis |
| title_full_unstemmed | Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis |
| title_short | Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis |
| title_sort | identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis |
| topic | 4T1Br4 Breast cancer Brain metastasis Syngeneic mouse model Histone deacetylase inhibitor |
| url | http://dmm.biologists.org/content/11/7/DMM034850 |
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