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FABP7 is a key metabolic regulator in HER2+ breast cancer brain metastasis

Abstract

Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer patients is associated with increased incidence of breast cancer brain metastases (BCBM), but the mechanisms underlying this phenomenon remain unclear. Here, to identify brain-predominant genes critical for the establishment of BCBM, we conducted an in silico screening analysis and identified that increased levels of fatty acid-binding protein 7 (FABP7) correlate with a lower survival and higher incidence of brain metastases in breast cancer patients. We validated these findings using HER2+ BCBM cells compared with parental breast cancer cells. Importantly, through knockdown and overexpression assays, we characterized the role of FABP7 in the BCBM process in vitro and in vivo. Our results uncover a key role of FABP7 in metabolic reprogramming of HER2 + breast cancer cells, supporting a glycolytic phenotype and storage of lipid droplets that enable their adaptation and survival in the brain microenvironment. In addition, FABP7 is shown to be required for upregulation of key metastatic genes and pathways, such as integrins-Src and VEGFA, and for the growth of HER2+ breast cancer cells in the brain microenvironment in vivo. Together, our results support FABP7 as a potential target for the treatment of HER2+ BCBM.

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Acknowledgements

We would like to thank Dr Katarzyna C. Pituch and Dr Diana Saleiro for helpful discussions during the preparation of this paper; Paul Joseph Mehl, Aurora Lopez-Rosas, and Northwestern University animal facility for their technical assistance. This work was supported by NIH grants R35CA197725, R01NS87990, R01NS093903 (MSL), and 1R01NS096376-01A1 (AUA).

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AC: conception and design, collection and/or assembly of data, data analysis and interpretation, paper writing, and editing of the paper. DK: conception and design, data analysis and interpretation, and editing of the paper. JM, WKP, AX, YH, NB, ZW, AA,TX, and MW: collection and/or assembly of data and final approval of the paper. MSL: conception and design, financial support, and final approval of the paper.

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Correspondence to Maciej S. Lesniak.

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Cordero, A., Kanojia, D., Miska, J. et al. FABP7 is a key metabolic regulator in HER2+ breast cancer brain metastasis. Oncogene 38, 6445–6460 (2019). https://doi.org/10.1038/s41388-019-0893-4

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