Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA.
Oncogene. 2019 Sep;38(37):6445-6460. doi: 10.1038/s41388-019-0893-4. Epub 2019 Jul 19.
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.
人表皮生长因子受体 2（HER2）在乳腺癌患者中的过表达与乳腺癌脑转移（BCBM）的发生率增加有关，但这一现象的潜在机制仍不清楚。在这里，为了确定对 BCBM 建立至关重要的脑部优势基因，我们进行了计算机筛选分析，发现脂肪酸结合蛋白 7（FABP7）水平的升高与乳腺癌患者的生存率降低和脑转移发生率升高相关。我们使用 HER2+BCBM 细胞与亲本乳腺癌细胞进行了验证。重要的是，通过敲低和过表达实验，我们在体外和体内研究了 FABP7 在 BCBM 过程中的作用。我们的研究结果揭示了 FABP7 在 HER2+乳腺癌细胞代谢重编程中的关键作用，支持了糖酵解表型和脂滴的储存，使它们能够适应和在脑微环境中存活。此外，研究结果表明 FABP7 是上调关键转移基因和途径（如整合素-Src 和 VEGFA）所必需的，也是 HER2+乳腺癌细胞在脑微环境中体内生长所必需的。综上所述，我们的研究结果支持 FABP7 作为治疗 HER2+BCBM 的潜在靶点。
