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EBP50 inhibits the migration and invasion of human breast cancer cells via LIMK/cofilin and the PI3K/Akt/mTOR/MMP signaling pathway

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Abstract

The scaffold protein ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50, also known as NHERF1 or NHERF) inhibits epidermal growth factor (EGF)-induced breast cancer cell proliferation after 3 days by blocking EGF receptor (EGFR) phosphorylation. The loss of EBP50 stimulates EGFR activity and induces the appearance of epithelial-to-mesenchymal transition phenotypic features in biliary cancer cells. However, the involvement of EBP50 in breast cancer migration and invasion remains unknown. We report that EBP50 inhibits the migration and invasion of breast cancer cells by inhibiting the phosphorylation of LIN-11, Isl1, and MEC-3 protein domain kinase, as well as cofilin. This phosphorylation is a critical step in cofilin recycling and actin polymerization mediating cytoskeletal rearrangement. Additionally, EGF-induced phosphorylation of Akt and mTOR was suppressed by upregulation of EBP50. Our results indicate that EBP50 is significantly involved in breast cancer invasion/metastasis via LIMK/cofilin and the PI3K/Akt/mTOR/MMP signaling pathway.

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References

  1. Malakoff D. Intellectual property. Patent reform shuffles who is first in line. Science. 2011;333(6049):1559–60. doi:10.1126/science.333.6049.1559.

    Article  PubMed  CAS  Google Scholar 

  2. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1559–64. doi:10.1126/science.1203543.

    Article  PubMed  CAS  Google Scholar 

  3. Liang X. EMT: new signals from the invasive front. Oral Oncol. 2011;47(8):686–7. doi:10.1016/j.oraloncology.2011.04.016.

    Article  PubMed  Google Scholar 

  4. Christofori G. New signals from the invasive front. Nature. 2006;441(7092):444–50.

    Article  PubMed  CAS  Google Scholar 

  5. Claperon A, Therrien M. KSR and CNK: two scaffolds regulating RAS-mediated RAF activation. Oncogene. 2007;26(22):3143–58. doi:10.1038/sj.onc.1210408.

    Article  PubMed  CAS  Google Scholar 

  6. Zheng JF, Sun LC, Liu H, Huang Y, Li Y, He J. EBP50 exerts tumor suppressor activity by promoting cell apoptosis and retarding extracellular signal-regulated kinase activity. Amino Acids. 2010;38(4):1261–8. doi:10.1007/s00726-009-0437-2.

    Article  PubMed  CAS  Google Scholar 

  7. Hayashi Y, Molina JR, Hamilton SR, Georgescu MM. NHERF1/EBP50 is a new marker in colorectal cancer. Neoplasia. 2010;12(12):1013–22.

    PubMed  CAS  PubMed Central  Google Scholar 

  8. Bartholow TL, Becich MJ, Chandran UR, Parwani AV. Immunohistochemical analysis of ezrin-radixin-moesin-binding phosphoprotein 50 in prostatic adenocarcinoma. BMC Urol. 2011;11:12. doi:10.1186/1471-2490-11-12.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Song J, Bai J, Yang W, Gabrielson EW, Chan DW, Zhang Z. Expression and clinicopathological significance of oestrogen-responsive ezrin-radixin-moesin-binding phosphoprotein 50 in breast cancer. Histopathology. 2007;51(1):40–53. doi:10.1111/j.1365-2559.2007.02730.x.

    Article  PubMed  CAS  Google Scholar 

  10. Pan Y, Wang L, Dai JL. Suppression of breast cancer cell growth by Na+/H+ exchanger regulatory factor 1 (NHERF1). Breast Cancer Res. 2006;8(6):R63. doi:10.1186/bcr1616.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yao W, Feng D, Bian W, Yang L, Li Y, Yang Z, Xiong Y, Zheng J, Zhai R, He J. EBP50 inhibits EGF-induced breast cancer cell proliferation by blocking EGFR phosphorylation. Amino Acids. 2012;43(5):2027–35. doi:10.1007/s00726-012-1277-z.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Fouassier L, Rosenberg P, Mergey M, Saubamea B, Claperon A, Kinnman N, Chignard N, Jacobsson-Ekman G, Strandvik B, Rey C, Barbu V, Hultcrantz R, Housset C. Ezrin-radixin-moesin-binding phosphoprotein (EBP50), an estrogen-inducible scaffold protein, contributes to biliary epithelial cell proliferation. Am J Pathol. 2009;174(3):869–80. doi:10.2353/ajpath.2009.080079.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Shibata T, Chuma M, Kokubu A, Sakamoto M, Hirohashi S. EBP50, a beta-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma. Hepatology. 2003;38(1):178–86. doi:10.1053/jhep.2003.50270.

    Article  PubMed  CAS  Google Scholar 

  14. Claperon A, Guedj N, Mergey M, Vignjevic D, Desbois-Mouthon C, Boissan M, Saubamea B, Paradis V, Housset C, Fouassier L. Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells. Oncogene. 2012;31(11):1376–88. doi:10.1038/onc.2011.334.

    Article  PubMed  CAS  Google Scholar 

  15. Shi L, Sun X, Zhang J, Zhao C, Li H, Liu Z, Fang C, Wang X, Zhang X, Zhou F, Lu S, Luo R, Zhang B. Gab2 expression in glioma and its implications for tumor invasion. Acta Oncol. 2012;. doi:10.3109/0284186X.2012.750032.

    PubMed  Google Scholar 

  16. Guo H, Gu F, Li W, Zhang B, Niu R, Fu L, Zhang N, Ma Y. Reduction of protein kinase C zeta inhibits migration and invasion of human glioblastoma cells. J Neurochem. 2009;109(1):203–13.

    Article  PubMed  CAS  Google Scholar 

  17. Sun R, Gao P, Chen L, Ma D, Wang J, Oppenheim JJ, Zhang N. Protein kinase C zeta is required for epidermal growth factor-induced chemotaxis of human breast cancer cells. Cancer Res. 2005;65(4):1433–41.

    Article  PubMed  CAS  Google Scholar 

  18. Li H, Yin C, Zhang B, Sun Y, Shi L, Liu N, Liang S, Lu S, Liu Y, Zhang J, Li F, Li W, Liu F, Sun L, Qi Y. PTTG1 promotes migration and invasion of human non-small cell lung cancer cells and is modulated by miR-186. Carcinogenesis. 2013;34(9):2145–55. doi:10.1093/carcin/bgt158.

    Article  PubMed  CAS  Google Scholar 

  19. Yamazaki D, Kurisu S, Takenawa T. Regulation of cancer cell motility through actin reorganization. Cancer Sci. 2005;96(7):379–86. doi:10.1111/j.1349-7006.2005.00062.x.

    Article  PubMed  CAS  Google Scholar 

  20. Bernard O. Lim kinases, regulators of actin dynamics. Int J Biochem Cell Biol. 2007;39(6):1071–6. doi:10.1016/j.biocel.2006.11.011.

    Article  PubMed  CAS  Google Scholar 

  21. DesMarais V, Ghosh M, Eddy R, Condeelis J. Cofilin takes the lead. J Cell Sci. 2005;118(Pt 1):19–26. doi:10.1242/jcs.01631.

    Article  PubMed  CAS  Google Scholar 

  22. Wang XF, Du J, Zhang TL, Zhou QM, Lu YY, Zhang H, Su SB. Inhibitory effects of PC-SPESII herbal extract on human breast cancer metastasis. Evid Based Complement Alternat Med. 2013;2013:894386. doi:10.1155/2013/894386.

    PubMed  PubMed Central  Google Scholar 

  23. Yin C, Li H, Zhang B, Liu Y, Lu G, Lu S, Sun L, Qi Y, Li X, Chen W. RAGE-binding S100A8/A9 promotes the migration and invasion of human breast cancer cells through actin polymerization and epithelial-mesenchymal transition. Breast Cancer Res Treat. 2013;142(2):297–309. doi:10.1007/s10549-013-2737-1.

    Article  PubMed  CAS  Google Scholar 

  24. Grunt TW, Mariani GL. Novel approaches for molecular targeted therapy of breast cancer: interfering with PI3K/AKT/mTOR signaling. Curr Cancer Drug Targets. 2013;13(2):188–204.

    Article  PubMed  CAS  Google Scholar 

  25. Jiang H, Shang X, Wu H, Gautam SC, Al-Holou S, Li C, Kuo J, Zhang L, Chopp M. Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J Exp Ther Oncol. 2009;8(1):25–33.

    PubMed  PubMed Central  Google Scholar 

  26. Yan B, Kong M, Chen S, Chen YH. VEGF stimulation enhances Livin protein synthesis through mTOR signaling. J Cell Biochem. 2010;111(5):1114–24. doi:10.1002/jcb.22797.

    Article  PubMed  CAS  Google Scholar 

  27. Lu S, Niu N, Guo H, Tang J, Guo W, Liu Z, Shi L, Sun T, Zhou F, Li H, Zhang J, Zhang B. ARK5 promotes glioma cell invasion, and its elevated expression is correlated with poor clinical outcome. Eur J Cancer. 2013;49(3):752–63. doi:10.1016/j.ejca.2012.09.018.

    Article  PubMed  CAS  Google Scholar 

  28. Cao B, Yang Y, Pan Y, Jia Y, Brock MV, Herman JG, Guo M. Epigenetic silencing of CXCL14 induced colorectal cancer migration and invasion. Discov Med. 2013;16(88):137–47.

    PubMed  CAS  PubMed Central  Google Scholar 

  29. Liu D, Guo H, Li Y, Xu X, Yang K, Bai Y. Association between polymorphisms in the promoter regions of matrix metalloproteinases (MMPs) and risk of cancer metastasis: a meta-analysis. PLoS ONE. 2012;7(2):e31251. doi:10.1371/journal.pone.0031251.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Chien CS, Shen KH, Huang JS, Ko SC, Shih YW. Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem. 2010;333(1–2):169–80. doi:10.1007/s11010-009-0217-z.

    Article  PubMed  CAS  Google Scholar 

  31. Chetty C, Lakka SS, Bhoopathi P, Rao JS. MMP-2 alters VEGF expression via alphaVbeta3 integrin-mediated PI3K/AKT signaling in A549 lung cancer cells. Int J Cancer. 2010;127(5):1081–95. doi:10.1002/ijc.25134.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. McAuliffe PF, Meric-Bernstam F, Mills GB, Gonzalez-Angulo AM. Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis. Clin Breast Cancer. 2010;10(Suppl 3):S59–65. doi:10.3816/CBC.2010.s.013.

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by The Young and Middle-Aged Scientists Research Awards Foundation of Shandong Province (BS2011YY060), Foundation of Shandong Educational Committee (J12LK03 and J13LK03).

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The authors declare no conflict of interest.

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Correspondence to Chonggao Yin.

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Hongli Li and Baogang Zhang contributed equally to this work.

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Li, H., Zhang, B., Liu, Y. et al. EBP50 inhibits the migration and invasion of human breast cancer cells via LIMK/cofilin and the PI3K/Akt/mTOR/MMP signaling pathway. Med Oncol 31, 162 (2014). https://doi.org/10.1007/s12032-014-0162-x

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  • DOI: https://doi.org/10.1007/s12032-014-0162-x

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