Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Oncogene volume 38, pages 6445–6460 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Leyland-Jones B. Human epidermal growth factor receptor 2-positive breast cancer and central nervous system metastases. J Clin Oncol. 2009;27:5278–86.

    Article  Google Scholar 

  2. Kodack DP, Askoxylakis V, Ferraro GB, Fukumura D, Jain RK. Emerging strategies for treating brain metastases from breast cancer. Cancer Cell. 2015;27:163–75.

    Article  CAS  Google Scholar 

  3. Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30:2585–92.

    Article  CAS  Google Scholar 

  4. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.

    Article  CAS  Google Scholar 

  5. Emi Y, Kitamura K, Shikada Y, Kakeji Y, Takahashi I, Tsutsui S. Metastatic breast cancer with HER2/neu-positive cells tends to have a morbid prognosis. Surgery. 2002;131:S217–21.

    Article  Google Scholar 

  6. Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 2011;11:263–75.

    Article  CAS  Google Scholar 

  7. Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, et al. Genes that mediate breast cancer metastasis to the brain. Nature. 2009;459:1005–9.

    Article  CAS  Google Scholar 

  8. Sihto H, Lundin J, Lundin M, Lehtimaki T, Ristimaki A, Holli K, et al. Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites: a nationwide cohort study. Breast Cancer Res. 2011;13:R87.

    Article  CAS  Google Scholar 

  9. Neman J, Termini J, Wilczynski S, Vaidehi N, Choy C, Kowolik CM. et al. Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proc Natl Acad Sci USA. 2014;111:984–9.

    Article  CAS  Google Scholar 

  10. Valiente M, Obenauf AC, Jin X, Chen Q, Zhang XH, Lee DJ, et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 2014;156:1002–16.

    Article  CAS  Google Scholar 

  11. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2:e1600200.

    Article  Google Scholar 

  12. Seyfried TN, Kiebish MA, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P. Metabolic management of brain cancer. Biochim Biophys Acta. 2011;1807:577–94.

    Article  CAS  Google Scholar 

  13. Thupari JN, Pinn ML, Kuhajda FP. Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity. Biochem Biophys Res Commun. 2001;285:217–23.

    Article  CAS  Google Scholar 

  14. Camarda R, Zhou AY, Kohnz RA, Balakrishnan S, Mahieu C, Anderton B, et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med. 2016;22:427–32.

    Article  CAS  Google Scholar 

  15. Park JH, Vithayathil S, Kumar S, Sung PL, Dobrolecki LE, Putluri V, et al. Fatty acid oxidation-driven Src links mitochondrial energy reprogramming and oncogenic properties in triple-negative breast cancer. Cell Rep. 2016;14:2154–65.

    Article  CAS  Google Scholar 

  16. Wang T, Fahrmann JF, Lee H, Li YJ, Tripathi SC, Yue C, et al. JAK/STAT3-regulated fatty acid beta-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. 2018;27:1357.

    Article  CAS  Google Scholar 

  17. Pascual G, Avgustinova A, Mejetta S, Martin M, Castellanos A, Attolini CS, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature. 2017;541:41–5.

    Article  CAS  Google Scholar 

  18. Storch J, Corsico B. The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Annu Rev Nutr. 2008;28:73–95.

    Article  CAS  Google Scholar 

  19. Bensaad K, Favaro E, Lewis CA, Peck B, Lord S, Collins JM, et al. Fatty acid uptake and lipid storage induced by HIF-1alpha contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep. 2014;9:349–65.

    Article  CAS  Google Scholar 

  20. van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009.

    Article  Google Scholar 

  21. Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M, et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell. 2009;16:67–78.

    Article  CAS  Google Scholar 

  22. Lamborn KR, Chang SM, Prados MD. Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis. Neuro Oncol. 2004;6:227–35.

    Article  Google Scholar 

  23. Zhang S, Huang WC, Zhang L, Zhang C, Lowery FJ, Ding Z, et al. SRC family kinases as novel therapeutic targets to treat breast cancer brain metastases. Cancer Res. 2013;73:5764–74.

    Article  CAS  Google Scholar 

  24. Kanojia D, Morshed RA, Zhang L, Miska JM, Qiao J, Kim JW, et al. βIII-tubulin regulates breast cancer metastases to the brain. Mol Cancer Ther. 2015;14:1152–61.

    Article  CAS  Google Scholar 

  25. Krakhmal NV, Zavyalova MV, Denisov EV, Vtorushin SV, Perelmuter VM. Cancer invasion: patterns and mechanisms. Acta Nat. 2015;7:17–28.

    Article  CAS  Google Scholar 

  26. Slipicevic A, Jorgensen K, Skrede M, Rosnes AK, Troen G, Davidson B, et al. The fatty acid binding protein 7 (FABP7) is involved in proliferation and invasion of melanoma cells. BMC Cancer. 2008;8:276.

    Article  Google Scholar 

  27. Martin TA, Jiang WG. Loss of tight junction barrier function and its role in cancer metastasis. Biochim Biophys Acta. 2009;1788:872–91.

    Article  CAS  Google Scholar 

  28. Dong G, Mao Q, Xia W, Xu Y, Wang J, Xu L, et al. PKM2 and cancer: The function of PKM2 beyond glycolysis. Oncol Lett. 2016;11:1980–6.

    Article  CAS  Google Scholar 

  29. Pelletier M, Billingham LK, Ramaswamy M, Siegel RM. Extracellular flux analysis to monitor glycolytic rates and mitochondrial oxygen consumption. Methods Enzym. 2014;542:125–49.

    Article  CAS  Google Scholar 

  30. Reily C, Mitchell T, Chacko BK, Benavides G, Murphy MP, Darley-Usmar V. Mitochondrially targeted compounds and their impact on cellular bioenergetics. Redox Biol. 2013;1:86–93.

    Article  CAS  Google Scholar 

  31. Kim HM, Jung WH, Koo JS. Site-specific metabolic phenotypes in metastatic breast cancer. J Transl Med. 2014;12:354.

    Article  Google Scholar 

  32. Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia. 2015;3:83–92.

    Article  Google Scholar 

  33. Koizume S, Miyagi Y. Lipid droplets: a key cellular organelle associated with cancer cell survival under normoxia and hypoxia. Int J Mol Sci. 2016;17:1430.

    Article  Google Scholar 

  34. Mitra SK, Schlaepfer DD. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006;18:516–23.

    Article  CAS  Google Scholar 

  35. LaGory EL, Giaccia AJ. The ever-expanding role of HIF in tumour and stromal biology. Nat Cell Biol. 2016;18:356–65.

    Article  CAS  Google Scholar 

  36. Gilkes DM, Bajpai S, Chaturvedi P, Wirtz D, Semenza GL. Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J Biol Chem. 2013;288:10819–29.

    Article  CAS  Google Scholar 

  37. Zhou Y, Jin G, Mi R, Zhang J, Zhang J, Xu H, et al. Knockdown of P4HA1 inhibits neovascularization via targeting glioma stem cell-endothelial cell transdifferentiation and disrupting vascular basement membrane. Oncotarget. 2017;8:35877–89.

    PubMed  PubMed Central  Google Scholar 

  38. Ciminera AK, Jandial R, Termini J. Metabolic advantages and vulnerabilities in brain metastases. Clin Exp Metastasis. 2017;34:401–10.

    Article  CAS  Google Scholar 

  39. Feng L, Hatten ME, Heintz N. Brain lipid-binding protein (BLBP): a novel signaling system in the developing mammalian CNS. Neuron. 1994;12:895–908.

    Article  CAS  Google Scholar 

  40. Haunerland NH, Spener F. Fatty acid-binding proteins–insights from genetic manipulations. Prog Lipid Res. 2004;43:328–49.

    Article  CAS  Google Scholar 

  41. Anthony TE, Mason HA, Gridley T, Fishell G, Heintz N. Brain lipid-binding protein is a direct target of Notch signaling in radial glial cells. Genes Dev. 2005;19:1028–33.

    Article  CAS  Google Scholar 

  42. Tang Z, Shen Q, Xie H, Zhou X, Li J, Feng J, et al. Elevated expression of FABP3 and FABP4 cooperatively correlates with poor prognosis in non-small cell lung cancer (NSCLC). Oncotarget. 2016;7:46253–62.

    PubMed  PubMed Central  Google Scholar 

  43. Guaita-Esteruelas S, Guma J, Masana L, Borras J. The peritumoural adipose tissue microenvironment and cancer. The roles of fatty acid binding protein 4 and fatty acid binding protein 5. Mol Cell Endocrinol. 2018;462:107–18.

    Article  CAS  Google Scholar 

  44. Liang Y, Diehn M, Watson N, Bollen AW, Aldape KD, Nicholas MK, et al. Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc Natl Acad Sci USA. 2005;102:5814–9.

    Article  CAS  Google Scholar 

  45. Kaloshi G, Mokhtari K, Carpentier C, Taillibert S, Lejeune J, Marie Y, et al. FABP7 expression in glioblastomas: relation to prognosis, invasion and EGFR status. J Neurooncol. 2007;84:245–8.

    Article  Google Scholar 

  46. Seliger B, Lichtenfels R, Atkins D, Bukur J, Halder T, Kersten M, et al. Identification of fatty acid binding proteins as markers associated with the initiation and/or progression of renal cell carcinoma. Proteomics. 2005;5:2631–40.

    Article  CAS  Google Scholar 

  47. Hao J, Zhang Y, Yan X, Yan F, Sun Y, Zeng J, et al. Circulating adipose fatty acid binding protein is a new link underlying obesity-associated breast/mammary tumor development. Cell Metab. 2018;28:689–705 e5.

    Article  CAS  Google Scholar 

  48. Hao J, Yan F, Zhang Y, Triplett A, Zhang Y, Schultz DA, et al. Expression of adipocyte/macrophage fatty acid-binding protein in tumor-associated macrophages promotes breast cancer progression. Cancer Res. 2018;78:2343–55.

    Article  CAS  Google Scholar 

  49. Pascual G, Dominguez D, Benitah SA. The contributions of cancer cell metabolism to metastasis. Dis Model Mech. 2018;11:1754–8411.

    Article  Google Scholar 

  50. Liu RZ, Graham K, Glubrecht DD, Lai R, Mackey JR, Godbout R. A fatty acid-binding protein 7/RXRbeta pathway enhances survival and proliferation in triple-negative breast cancer. J Pathol. 2012;228:310–21.

    Article  CAS  Google Scholar 

  51. Zhang Y, Sun Y, Rao E, Yan F, Li Q, Zhang Y, et al. Fatty acid-binding protein E-FABP restricts tumor growth by promoting IFN-beta responses in tumor-associated macrophages. Cancer Res. 2014;74:2986–98.

    Article  CAS  Google Scholar 

  52. Stivarou T, Patsavoudi E. Extracellular molecules involved in cancer cell invasion. Cancers. 2015;7:238–65.

    Article  CAS  Google Scholar 

  53. Thakur R, Trivedi R, Rastogi N, Singh M, Mishra DP. Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer. Sci Rep. 2015;5:10194.

    Article  CAS  Google Scholar 

  54. Feng Y, Spezia M, Huang S, Yuan C, Zeng Z, Zhang L, et al. Breast cancer development and progression: risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis. 2018;5:77–106.

    Article  CAS  Google Scholar 

  55. Chlenski A, Ketels KV, Korovaitseva GI, Talamonti MS, Oyasu R, Scarpelli DG. Organization and expression of the human zo-2 gene (tjp-2) in normal and neoplastic tissues. Biochim Biophys Acta. 2000;1493:319–24.

    Article  CAS  Google Scholar 

  56. Liu KC, Cheney RE. Myosins in cell junctions. Bioarchitecture. 2012;2:158–70.

    Article  Google Scholar 

  57. Chua J, Rikhy R, Lippincott-Schwartz J. Dynamin 2 orchestrates the global actomyosin cytoskeleton for epithelial maintenance and apical constriction. Proc Natl Acad Sci USA. 2009;106:20770–5.

    Article  CAS  Google Scholar 

  58. Bennett V, Healy J. Membrane domains based on ankyrin and spectrin associated with cell-cell interactions. Cold Spring Harb Perspect Biol. 2009;1:a003012.

    Article  Google Scholar 

  59. Martin TA, Watkins G, Mansel RE, Jiang WG. Loss of tight junction plaque molecules in breast cancer tissues is associated with a poor prognosis in patients with breast cancer. Eur J Cancer 2004;40:2717–25.

    Article  CAS  Google Scholar 

  60. Marie SK, Shinjo SM. Metabolism and brain cancer. Clinics. 2011;66:33–43.

    Article  Google Scholar 

  61. Han T, Kang D, Ji D, Wang X, Zhan W, Fu M, et al. How does cancer cell metabolism affect tumor migration and invasion? Cell Adhes Migr. 2013;7:395–403.

    Article  Google Scholar 

  62. Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 2006;66:5216–23.

    Article  CAS  Google Scholar 

  63. Talasila KM, Rosland GV, Hagland HR, Eskilsson E, Flones IH, Fritah S, et al. The angiogenic switch leads to a metabolic shift in human glioblastoma. Neuro Oncol. 2017;19:383–93.

    CAS  PubMed  Google Scholar 

  64. Desai S, Ding M, Wang B, Lu Z, Zhao Q, Shaw K, et al. Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers. Oncotarget. 2014;5:8202–10.

    Article  Google Scholar 

  65. Nguyen A, Loo JM, Mital R, Weinberg EM, Man FY, Zeng Z, et al. PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis. J Clin Investig. 2016;126:681–94.

    Article  Google Scholar 

  66. Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogenesis. 2016;5:e189.

    Article  CAS  Google Scholar 

  67. Cheng C, Edin NF, Lauritzen KH, Aspmodal I, Christoffersen S, Jian L, et al. Alterations of monocarboxylate transporter densities during hypoxia in brain and breast tumour cells. Cell Oncol. 2012;35:217–27.

    Article  CAS  Google Scholar 

  68. Sjobakk TE, Vettukattil R, Gulati M, Gulati S, Lundgren S, Gribbestad IS, et al. Metabolic profiles of brain metastases. Int J Mol Sci. 2013;14:2104–18.

    Article  Google Scholar 

  69. Kanojia D, Balyasnikova IV, Morshed RA, Frank RT, Yu D, Zhang L, et al. Neural stem cells secreting anti-HER2 antibody improve survival in a preclinical model of HER2 overexpressing breast cancer brain metastases. Stem Cells. 2015;33:2985–94.

    Article  CAS  Google Scholar 

  70. Miska J, Lee-Chang C, Rashidi A, Muroski ME, Chang AL, Lopez-Rosas A, et al. HIF-1alpha is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep. 2019;27:226–37 e4.

    Article  CAS  Google Scholar 

  71. Listenberger LL, Studer AM, Brown DA, Wolins NE. Fluorescent detection of lipid droplets and associated proteins. Curr Protoc Cell Biol. 2016;71:4 31 1-4 14

    Google Scholar 

  72. Enerly E, Steinfeld I, Kleivi K, Leivonen SK, Aure MR, Russnes HG, et al. miRNA-mRNA integrated analysis reveals roles for miRNAs in primary breast tumors. PLoS ONE. 2011;6:e16915.

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Alex Cordero, Deepak Kanojia, Jason Miska, Wojciech K. Panek, Annie Xiao, Yu Han, Nicolas Bonamici, Ting Xiao, Meijing Wu, Atique U. Ahmed & Maciej S. Lesniak

  2. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA

    Weidong Zhou

Authors
  1. Alex Cordero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deepak Kanojia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jason Miska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wojciech K. Panek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Annie Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nicolas Bonamici
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weidong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ting Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Meijing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Atique U. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Maciej S. Lesniak
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Maciej S. Lesniak.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0893-4

This article is cited by

Search

Advanced search

Quick links