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Journal of Molecular Medicine

, Volume 92, Issue 1, pp 13–30 | Cite as

Metastasis suppressors in breast cancers: mechanistic insights and clinical potential

  • Christopher R. Bohl
  • Sitaram Harihar
  • Warren L. Denning
  • Rahul Sharma
  • Danny R. WelchEmail author
Review

Abstract

For the most part, normal epithelial cells do not disseminate to other parts of the body and proliferate, as do metastatic cells. Presumably, a class of molecules—termed metastasis suppressors—are involved in this homeostatic control. Metastasis suppressors are, by definition, cellular factors that, when re-expressed in metastatic cells, functionally inhibit metastasis without significantly inhibiting tumor growth. In this brief review, we catalog known metastasis suppressors, what is known about their mechanism(s) of action, and experimental and clinical associations to date.

Keywords

Metastasis suppressor Nm23 BRMS1 KISS1 TIMP E-cadherin MKK4/6 KAI1 Adhesion Invasion MMP Intravasation Cohesion Motility Endothelium Angiogenesis Review 

Notes

Acknowledgments

Work from the authors’ laboratory has been generously supported by grants from US National Cancer Institute RO1-CA134981 (DRW), Susan G. Komen for the Cure SAC11037 (DRW), National Foundation for Cancer Research-Center for Metastasis Research (DRW), and partial support from the Kansas Bioscience Authority (DRW), RO1-CA87728 (DRW), and P30-CA168524 (DRW). DRW is the Hall Family Foundation Professor of Molecular Medicine and a Kansas Bioscience Authority Eminent Scholar.

Conflict of interest

The authors have no conflicts to declare.

References

  1. 1.
    Smith SC, Theodorescu D (2009) Learning therapeutic lessons from metastasis suppressor proteins. Nat Rev Cancer 9:253–264PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12:895–904PubMedCrossRefGoogle Scholar
  3. 3.
    Steeg PS, Bevilacqua G, Pozzatti R, Liotta LA, Sobel ME (1988) Altered expression of NM23, a gene associated with low tumor metastatic potential, during adenovirus 2 Ela inhibition of experimental metastasis. Cancer Res 48:6550–6554PubMedGoogle Scholar
  4. 4.
    Marino N, Marshall JC, Steeg PS (2011) Protein–protein interactions: a mechanism regulating the anti-metastatic properties of Nm23-H1. Naunyn Schmiedebergs Arch Pharmacol 384:351–362PubMedCrossRefGoogle Scholar
  5. 5.
    Steeg PS, Horak CE, Miller KD (2008) Clinical-translational approaches to the Nm23-H1 metastasis suppressor. Clin Cancer Res 14:5006–5012PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Ouatas T, Halverson D, Steeg PS (2003) Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor gene expression in metastatic human breast carcinoma cells: new uses for old compounds. Clin Cancer Res 9:3763–3772PubMedGoogle Scholar
  7. 7.
    Palmieri D, Halverson DO, Ouatas T, Horak CE, Salerno M, Johnson J, Figg WD, Hollingshead M, Hursting S, Berrigan D et al (2005) Medroxyprogesterone acetate elevation of Nm23-H1 metastasis suppressor expression in hormone receptor-negative breast cancer. J Natl Cancer Inst 97:632–642PubMedCrossRefGoogle Scholar
  8. 8.
    Hurst DR, Welch DR (2011) Unraveling the enigmatic complexities of BRMS1-mediated metastasis suppression. FEBS Lett 585:3185–3190PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Edmonds MD, Hurst DR, Vaidya KS, Stafford LJ, Chen D, Welch DR (2009) Breast cancer metastasis suppressor 1 coordinately regulates metastasis-associated microRNA expression. Int J Cancer 125:1778–1785PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Slipicevic A, Holm R, Emilsen E, Ree Rosnes AK, Welch DR, Maelandsmo GM, Florenes VA (2012) Cytoplasmic BRMS1 expression in malignant melanoma is associated with increased disease-free survival. BMC Cancer 12:73PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Frolova N, Edmonds MD, Bodenstine TM, Seitz R, Johnson MR, Feng R, Welch DR, Frost AR (2009) A shift from nuclear to cytoplasmic breast cancer metastasis suppressor 1 expression is associated with highly proliferative estrogen receptor-negative breast cancers. Tumour Biol 30:148–159PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang Z, Yamashita H, Toyama T, Yamamoto Y, Kawasoe T, Iwase H (2006) Reduced expression of the breast cancer metastasis suppressor 1 mRNA is correlated with poor progress in breast cancer. Clin Cancer Res 12:6410–6414PubMedCrossRefGoogle Scholar
  13. 13.
    Fujita H, Okada F, Hamada J, Hosokawa M, Moriuchi T, Koya RC, Kuzumaki N (2001) Gelsolin functions as a metastasis suppressor in B16-BL6 mouse melanoma cells and requirement of the carboxyl-terminus for its effect. Int J Cancer 93:773–780PubMedCrossRefGoogle Scholar
  14. 14.
    Baig RM, Mahjabeen I, Sabir M, Masood N, Ali K, Malik FA, Kayani MA (2013) Mutational spectrum of Gelsolin and its down regulation is associated with breast cancer. Disease markers 34:71–80PubMedCrossRefGoogle Scholar
  15. 15.
    Ichikawa T, Ichikawa Y, Dong J, Hawkins AL, Griffin CA, Isaacs WB, Oshimura M, Barrett JC, Isaacs JT (1992) Localization of metastasis suppressor gene(s) for prostatic cancer to the short arm of human chromosome 11. Cancer Res 52:3486–3490PubMedGoogle Scholar
  16. 16.
    Liu WM, Zhang XA (2006) KAI1/CD82, a tumor metastasis suppressor. Cancer letters 240:183–194PubMedCrossRefGoogle Scholar
  17. 17.
    Malik FA, Sanders AJ, Jiang WG (2009) KAI-1/CD82, the molecule and clinical implication in cancer and cancer metastasis. Histol Histopathol 24:519–530PubMedGoogle Scholar
  18. 18.
    Tsai YC, Weissman AM (2011) Dissecting the diverse functions of the metastasis suppressor CD82/KAI1. FEBS Lett 585:3166–3173PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Chairoungdua A, Smith DL, Pochard P, Hull M, Caplan MJ (2010) Exosome release of beta-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol 190:1079–1091PubMedCrossRefGoogle Scholar
  20. 20.
    Beck BH, Welch DR (2010) The KISS1 metastasis suppressor: a good night kiss for disseminated cancer cells. Eur J Cancer 46:1283–1289PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Vander Griend DJ, Kocherginsky M, Hickson JA, Stadler WM, Lin A, Rinker-Schaeffer CW (2005) Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. Cancer Res 65:10984–10991PubMedCrossRefGoogle Scholar
  22. 22.
    Hickson JA, Huo D, Vander Griend DJ, Lin A, Rinker-Schaeffer CW, Yamada SD (2006) The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Cancer Res 66:2264–2270PubMedCrossRefGoogle Scholar
  23. 23.
    Huang MJ, Wang PN, Huang J, Zhang XW, Wang L, Liu HL, Wang JP (2013) Expression and clinicopathological significance of serine257/threonine261 phosphorylated MKK4 in colorectal carcinoma. Zhonghua Yi Xue Za Zhi 93:746–750PubMedGoogle Scholar
  24. 24.
    Seraj MJ, Samant RS, Verderame MF, Welch DR (2000) Functional evidence for a novel human breast carcinoma metastasis suppressor, BRMS1, encoded at chromosome 11q13. Cancer Res 60:2764–2769PubMedGoogle Scholar
  25. 25.
    Gildea JJ, Seraj MJ, Oxford G, Harding MA, Hampton GM, Moskaluk CA, Frierson HF, Conaway MR, Theodorescu D (2002) RhoGDI2 is an invasion and metastasis suppressor gene in human cancer. Cancer Res 62:6418–6423PubMedGoogle Scholar
  26. 26.
    Griner EM, Theodorescu D (2012) The faces and friends of RhoGDI2. Cancer Metastasis Rev 31:519–528PubMedCrossRefGoogle Scholar
  27. 27.
    DerMardirossian C, Bokoch GM (2005) GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol 15:356–363PubMedCrossRefGoogle Scholar
  28. 28.
    Wu Y, Moissoglu K, Wang H, Wang X, Frierson HF, Schwartz MA, Theodorescu D (2009) Src phosphorylation of RhoGDI2 regulates its metastasis suppressor function. Proc Natl Acad Sci U S A 106:5807–5812PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Griner EM, Churchill ME, Brautigan DL, Theodorescu D (2013) PKCalpha phosphorylation of RhoGDI2 at Ser31 disrupts interactions with Rac1 and decreases GDI activity. Oncogene 32:1010–1017PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Moissoglu K, McRoberts KS, Meier JA, Theodorescu D, Schwartz MA (2009) Rho GDP dissociation inhibitor 2 suppresses metastasis via unconventional regulation of RhoGTPases. Cancer Res 69:2838–2844PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Yuan BZ, Miller MJ, Keck CL, Zimonjic DB, Thorgeirsson SS, Popescu NC (1998) Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. Cancer Res 58:2196–2199PubMedGoogle Scholar
  32. 32.
    Goodison S, Yuan J, Sloan D, Kim R, Li C, Popescu NC, Urquidi V (2005) The RhoGAP protein DLC-1 functions as a metastasis suppressor in breast cancer cells. Cancer Res 65:6042–6053PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Ko FC, Chan LK, Tung EK, Lowe SW, Ng IO, Yam JW (2010) Akt phosphorylation of deleted in liver cancer 1 abrogates its suppression of liver cancer tumorigenesis and metastasis. Gastroenterology 139:1397–1407PubMedCrossRefGoogle Scholar
  34. 34.
    Scholz RP, Regner J, Theil A, Erlmann P, Holeiter G, Jahne R, Schmid S, Hausser A, Olayioye MA (2009) DLC1 interacts with 14-3-3 proteins to inhibit RhoGAP activity and block nucleocytoplasmic shuttling. J Cell Sci 122:92–102PubMedCrossRefGoogle Scholar
  35. 35.
    Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45PubMedCrossRefGoogle Scholar
  36. 36.
    Goodison S, Urquidi V, Tarin D (1999) CD44 cell adhesion molecules. Mol Pathol 52:189–196PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Thorne RF, Legg JW, Isacke CM (2004) The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events. J Cell Sci 117:373–380PubMedCrossRefGoogle Scholar
  38. 38.
    Louderbough JM, Schroeder JA (2011) Understanding the dual nature of CD44 in breast cancer progression. Mol Cancer Res 9:1573–1586PubMedCrossRefGoogle Scholar
  39. 39.
    Lopez JI, Camenisch TD, Stevens MV, Sands BJ, McDonald J, Schroeder JA (2005) CD44 attenuates metastatic invasion during breast cancer progression. Cancer Res 65:6755–6763PubMedCrossRefGoogle Scholar
  40. 40.
    Faraji F, Pang Y, Walker RC, Nieves Borges R, Yang L, Hunter KW (2012) Cadm1 is a metastasis susceptibility gene that suppresses metastasis by modifying tumor interaction with the cell-mediated immunity. PLoS genetics 8:e1002926PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Iwakuma T, Lozano G (2003) MDM2, an introduction. Mol Cancer Res 1:993–1000PubMedGoogle Scholar
  42. 42.
    Agarwal N, Adhikari AS, Iyer SV, Hekmatdoost K, Welch DR, Iwakuma T (2013) MTBP suppresses cell migration and filopodia formation by inhibiting ACTN4. Oncogene 32:462–470PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Agarwal N, Tochigi Y, Adhikari AS, Cui S, Cui Y, Iwakuma T (2011) MTBP plays a crucial role in mitotic progression and chromosome segregation. Cell Death Differ 18:1208–1219PubMedCrossRefGoogle Scholar
  44. 44.
    Teitz T, Stupack DG, Lahti JM (2006) Halting neuroblastoma metastasis by controlling integrin-mediated death. Cell Cycle 5:681–685PubMedCrossRefGoogle Scholar
  45. 45.
    Gao X, Pang J, Li LY, Liu WP, Di JM, Sun QP, Fang YQ, Liu XP, Pu XY, He D et al (2010) Expression profiling identifies new function of collapsin response mediator protein 4 as a metastasis-suppressor in prostate cancer. Oncogene 29:4555–4566PubMedCrossRefGoogle Scholar
  46. 46.
    Rodrigues S, De Wever O, Bruyneel E, Rooney RJ, Gespach C (2007) Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis. Oncogene 26:5615–5625PubMedCrossRefGoogle Scholar
  47. 47.
    Zhang Y, Edwards PA (2008) FXR signaling in metabolic disease. FEBS Lett 582:10–18PubMedCrossRefGoogle Scholar
  48. 48.
    Deuschle U, Schuler J, Schulz A, Schluter T, Kinzel O, Abel U, Kremoser C (2012) FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model. PLoS One 7:e43044PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Guan B, Li H, Yang Z, Hoque A, Xu X (2013) Inhibition of farnesoid X receptor controls esophageal cancer cell growth in vitro and in nude mouse xenografts. Cancer 119:1321–1329PubMedCrossRefGoogle Scholar
  50. 50.
    Lee JY, Lee KT, Lee JK, Lee KH, Jang KT, Heo JS, Choi SH, Kim Y, Rhee JC (2011) Farnesoid X receptor, overexpressed in pancreatic cancer with lymph node metastasis promotes cell migration and invasion. Br J Cancer 104:1027–1037PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Yang S, Lee KT, Lee JY, Lee JK, Lee KH, Rhee JC (2013) Inhibition of SCAMP1 suppresses cell migration and invasion in human pancreatic and gallbladder cancer cells. Tumour Biol 34:2731–2739PubMedCrossRefGoogle Scholar
  52. 52.
    Gobeil S, Zhu X, Doillon CJ, Green MR (2008) A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene. Genes Dev 22:2932–2940PubMedCrossRefGoogle Scholar
  53. 53.
    Martinelli DC, Fan CM (2007) Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev 21:1231–1243PubMedCrossRefGoogle Scholar
  54. 54.
    Anastas JN, Moon RT (2013) WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 13:11–26PubMedCrossRefGoogle Scholar
  55. 55.
    Klaus A, Birchmeier W (2008) Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8:387–398PubMedCrossRefGoogle Scholar
  56. 56.
    Briscoe J, Therond PP (2013) The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 14:416–429PubMedCrossRefGoogle Scholar
  57. 57.
    Milla LA, Gonzalez-Ramirez CN, Palma V (2012) Sonic Hedgehog in cancer stem cells: a novel link with autophagy. Biol Res 45:223–230PubMedCrossRefGoogle Scholar
  58. 58.
    Ma L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D, Teruya-Feldstein J, Reinhardt F, Onder TT, Valastyan S et al (2010) miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 12:247–256PubMedCentralPubMedGoogle Scholar
  59. 59.
    Chen D, Sun Y, Wei Y, Zhang P, Rezaeian AH, Teruya-Feldstein J, Gupta S, Liang H, Lin HK, Hung MC et al (2012) LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker. Nat Med 18:1511–1517PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Iorns E, Ward TM, Dean S, Jegg A, Thomas D, Murugaesu N, Sims D, Mitsopoulos C, Fenwick K, Kozarewa I et al (2012) Whole genome in vivo RNAi screening identifies the leukemia inhibitory factor receptor as a novel breast tumor suppressor. Breast Cancer Res Treat 135:79–91PubMedCrossRefGoogle Scholar
  61. 61.
    Dangi-Garimella S, Yun J, Eves EM, Newman M, Erkeland SJ, Hammond SM, Minn AJ, Rosner MR (2009) Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO J 28:347–358PubMedCrossRefGoogle Scholar
  62. 62.
    Martinho O, Pinto F, Granja S, Miranda-Goncalves V, Moreira MA, Ribeiro LF, di Loreto C, Rosner MR, Longatto-Filho A, Reis RM (2013) RKIP inhibition in cervical cancer is associated with higher tumor aggressive behavior and resistance to cisplatin therapy. PLoS One 8:e59104PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Das SK, Bhutia SK, Sokhi UK, Azab B, Su ZZ, Boukerche H, Anwar T, Moen EL, Chatterjee D, Pellecchia M et al (2012) Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma. Cancer Res 72:6217–6226PubMedCrossRefGoogle Scholar
  64. 64.
    Fu Z, Smith PC, Zhang L, Rubin MA, Dunn RL, Yao Z, Keller ET (2003) Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J Natl Cancer Inst 95:878–889PubMedCrossRefGoogle Scholar
  65. 65.
    Afonso J, Longatto-Filho A, Martinho O, Lobo F, Amaro T, Reis RM, Santos LL (2013) Low RKIP expression associates with poor prognosis in bladder cancer patients. Virchows Arch 462:445–453PubMedCrossRefGoogle Scholar
  66. 66.
    Song SP, Zhang SB, Li ZH, Zhou YS, Li B, Bian ZW, Liao QD, Zhang YD (2012) Reduced expression of Raf kinase inhibitor protein correlates with poor prognosis in pancreatic cancer. Clin Transl Oncol 14:848–852PubMedCrossRefGoogle Scholar
  67. 67.
    Yan H, Guoqiang L, Shengxi C, Zhenghao D, Lingjin H (2012) Reduction of Raf kinase inhibitor protein expression is associated with lymph node metastasis in resectable non-small cell lung cancer. Open Respir Med J 6:135–138PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Martinho O, Granja S, Jaraquemada T, Caeiro C, Miranda-Goncalves V, Honavar M, Costa P, Damasceno M, Rosner MR, Lopes JM et al (2012) Downregulation of RKIP is associated with poor outcome and malignant progression in gliomas. PLoS One 7:e30769PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Moon A, Park JY, Sung JY, Park YK, Kim YW (2012) Reduced expression of Raf-1 kinase inhibitory protein in renal cell carcinoma: a significant prognostic marker. Pathology 44:534–539PubMedCrossRefGoogle Scholar
  70. 70.
    Huang L, Dai T, Lin X, Zhao X, Chen X, Wang C, Li X, Shen H, Wang X (2012) MicroRNA-224 targets RKIP to control cell invasion and expression of metastasis genes in human breast cancer cells. Biochem Biophys Res Commun 425:127–133PubMedCrossRefGoogle Scholar
  71. 71.
    Bepler G, O’Briant KC, Kim YC, Schreiber G, Pitterle DM (1999) A 1.4-Mb high-resolution physical map and contig of chromosome segment 11p15.5 and genes in the LOH11A metastasis suppressor region. Genomics 55:164–175PubMedCrossRefGoogle Scholar
  72. 72.
    O’Briant KC, Bepler G (1997) Delineation of the centromeric and telomeric chromosome segment 11p15.5 lung cancer suppressor regions LOH11A and LOH11B. Genes Chromosomes Cancer 18:111–114PubMedCrossRefGoogle Scholar
  73. 73.
    Pitterle DM, Kim YC, Jolicoeur EM, Cao Y, O’Briant KC, Bepler G (1999) Lung cancer and the human gene for ribonucleotide reductase subunit M1 (RRM1). Mamm Genome 10:916–922PubMedCrossRefGoogle Scholar
  74. 74.
    Li W, Ding F, Zhang L, Liu Z, Wu Y, Luo A, Wu M, Wang M, Zhan Q, Liu Z (2005) Overexpression of stefin A in human esophageal squamous cell carcinoma cells inhibits tumor cell growth, angiogenesis, invasion, and metastasis. Clin Cancer Res 11:8753–8762PubMedCrossRefGoogle Scholar
  75. 75.
    Parker BS, Ciocca DR, Bidwell BN, Gago FE, Fanelli MA, George J, Slavin JL, Moller A, Steel R, Pouliot N et al (2008) Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer. J Pathol 214:337–346PubMedCrossRefGoogle Scholar
  76. 76.
    Bervar A, Zajc I, Sever N, Katunuma N, Sloane BF, Lah TT (2003) Invasiveness of transformed human breast epithelial cell lines is related to cathepsin B and inhibited by cysteine proteinase inhibitors. Biol Chem 384:447–455PubMedCrossRefGoogle Scholar
  77. 77.
    Okuda T, Kondoh H (1999) Identification of new genes ndr2 and ndr3 which are related to Ndr1/RTP/Drg1 but show distinct tissue specificity and response to N-myc. Biochem Biophys Res Commun 266:208–215PubMedCrossRefGoogle Scholar
  78. 78.
    Zhou RH, Kokame K, Tsukamoto Y, Yutani C, Kato H, Miyata T (2001) Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. Genomics 73:86–97PubMedCrossRefGoogle Scholar
  79. 79.
    Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB (2000) Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res 60:749–755PubMedGoogle Scholar
  80. 80.
    Bandyopadhyay S, Pai SK, Gross SC, Hirota S, Hosobe S, Miura K, Saito K, Commes T, Hayashi S, Watabe M et al (2003) The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res 63:1731–1736PubMedGoogle Scholar
  81. 81.
    Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Takano Y, Saito K, Piquemal D, Commes T, Watabe M, Gross SC et al (2004) Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene 23:5675–5681PubMedCrossRefGoogle Scholar
  82. 82.
    Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Tsukada T, Miura K, Takano Y, Saito K, Commes T, Piquemal D et al (2004) PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer. Cancer Res 64:7655–7660PubMedCrossRefGoogle Scholar
  83. 83.
    Ellen TP, Ke Q, Zhang P, Costa M (2008) NDRG1, a growth and cancer related gene: regulation of gene expression and function in normal and disease states. Carcinogenesis 29:2–8PubMedCrossRefGoogle Scholar
  84. 84.
    Kovacevic Z, Chikhani S, Lui GY, Sivagurunathan S, Richardson DR (2013) The iron-regulated metastasis suppressor NDRG1 targets NEDD4L, PTEN, and SMAD4 and inhibits the PI3K and Ras signaling pathways. Antioxid Redox Signal 18:874–887PubMedCrossRefGoogle Scholar
  85. 85.
    Stein S, Thomas EK, Herzog B, Westfall MD, Rocheleau JV, Jackson RS 2nd, Wang M, Liang P (2004) NDRG1 is necessary for p53-dependent apoptosis. J Biol Chem 279:48930–48940PubMedCrossRefGoogle Scholar
  86. 86.
    Zhang P, Tchou-Wong KM, Costa M (2007) Egr-1 mediates hypoxia-inducible transcription of the NDRG1 gene through an overlapping Egr-1/Sp1 binding site in the promoter. Cancer Res 67:9125–9133PubMedCrossRefGoogle Scholar
  87. 87.
    Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA, Lee SW (1998) Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer Res 58:4439–4444PubMedGoogle Scholar
  88. 88.
    Song Y, Lv L, Du J, Yue L, Cao L (2013) Correlation of N-myc downstream-regulated gene 1 subcellular localization and lymph node metastases of colorectal neoplasms. Biochem Biophys Res Commun 439:241–246PubMedCrossRefGoogle Scholar
  89. 89.
    Liu W, Xing F, Iiizumi-Gairani M, Okuda H, Watabe M, Pai SK, Pandey PR, Hirota S, Kobayashi A, Mo YY et al (2012) N-myc downstream regulated gene 1 modulates Wnt-beta-catenin signalling and pleiotropically suppresses metastasis. EMBO Mol Med 4:93–108PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Ando T, Ishiguro H, Kimura M, Mitsui A, Kurehara H, Sugito N, Tomoda K, Mori R, Takashima N, Ogawa R et al (2006) Decreased expression of NDRG1 is correlated with tumor progression and poor prognosis in patients with esophageal squamous cell carcinoma. Dis Esophagus 19:454–458PubMedCrossRefGoogle Scholar
  91. 91.
    Dos Santos M, da Cunha Mercante AM, Nunes FD, Leopoldino AM, de Carvalho MB, Gazito D, Lopez RV, Chiappini PB, de Carvalho Neto PB et al (2012) Prognostic significance of NDRG1 expression in oral and oropharyngeal squamous cell carcinoma. Mol Biol Rep 39:10157–10165PubMedCrossRefGoogle Scholar
  92. 92.
    Li Q, Chen H (2011) Transcriptional silencing of N-Myc downstream-regulated gene 1 (NDRG1) in metastatic colon cancer cell line SW620. Clin Exp Metastasis 28:127–135PubMedCrossRefGoogle Scholar
  93. 93.
    Mao Z, Sun J, Feng B, Ma J, Zang L, Dong F, Zhang D, Zheng M (2013) The metastasis suppressor, N-myc downregulated gene 1 (NDRG1), is a prognostic biomarker for human colorectal cancer. PLoS One 8:e68206PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Maruyama Y, Ono M, Kawahara A, Yokoyama T, Basaki Y, Kage M, Aoyagi S, Kinoshita H, Kuwano M (2006) Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis. Cancer Res 66:6233–6242PubMedCrossRefGoogle Scholar
  95. 95.
    Matsushita K, Uchida K, Saigusa S, Ide S, Hashimoto K, Koike Y, Otake K, Inoue M, Tanaka K, Kusunoki M (2013) Low NDRG1 mRNA expression predicts a poor prognosis in neuroblastoma patients. Pediatr Surg Int 29:363–368PubMedCrossRefGoogle Scholar
  96. 96.
    Strzelczyk B, Szulc A, Rzepko R, Kitowska A, Skokowski J, Szutowicz A, Pawelczyk T (2009) Identification of high-risk stage II colorectal tumors by combined analysis of the NDRG1 gene expression and the depth of tumor invasion. Ann Surg Oncol 16:1287–1294PubMedCrossRefGoogle Scholar
  97. 97.
    Sun B, Chu D, Li W, Chu X, Li Y, Wei D, Li H (2009) Decreased expression of NDRG1 in glioma is related to tumor progression and survival of patients. J Neurooncol 94:213–219PubMedCrossRefGoogle Scholar
  98. 98.
    Lin X, Tombler E, Nelson PJ, Ross M, Gelman IH (1996) A novel src- and ras-suppressed protein kinase C substrate associated with cytoskeletal architecture. J Biol Chem 271:28430–28438PubMedCrossRefGoogle Scholar
  99. 99.
    Gelman IH (2012) Suppression of tumor and metastasis progression through the scaffolding functions of SSeCKS/Gravin/AKAP12. Cancer Metastasis Rev 31:493–500PubMedCrossRefGoogle Scholar
  100. 100.
    Xia W, Unger P, Miller L, Nelson J, Gelman IH (2001) The Src-suppressed C kinase substrate, SSeCKS, is a potential metastasis inhibitor in prostate cancer. Cancer Res 61:5644–5651PubMedGoogle Scholar
  101. 101.
    Su B, Zheng Q, Vaughan MM, Bu Y, Gelman IH (2006) SSeCKS metastasis-suppressing activity in MatLyLu prostate cancer cells correlates with vascular endothelial growth factor inhibition. Cancer Res 66:5599–5607PubMedCrossRefGoogle Scholar
  102. 102.
    Behrens J, Birchmeier W, Goodman SL, Imhof BA (1985) Dissociation of Madin-Darby canine kidney epithelial cells by the monoclonal antibody anti-arc-1: mechanistic aspects and identification of the antigen as a component related to uvomorulin. J Cell Biol 101:1307–1315PubMedCrossRefGoogle Scholar
  103. 103.
    Behrens J, Mareel MM, Van Roy FM, Birchmeier W (1989) Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell–cell adhesion. J Cell Biol 108:2435–2447PubMedCrossRefGoogle Scholar
  104. 104.
    Vleminckx K, Vakaet L Jr, Mareel M, Fiers W, van Roy F (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66:107–119PubMedCrossRefGoogle Scholar
  105. 105.
    Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Lochner D, Birchmeier W (1991) E-cadherin-mediated cell–cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113:173–185PubMedCrossRefGoogle Scholar
  106. 106.
    Navarro P, Gomez M, Pizarro A, Gamallo C, Quintanilla M, Cano A (1991) A role for the E-cadherin cell–cell adhesion molecule during tumor progression of mouse epidermal carcinogenesis. J Cell Biol 115:517–533PubMedCrossRefGoogle Scholar
  107. 107.
    Geiger TR, Peeper DS (2009) Metastasis mechanisms. Biochim Biophys Acta 1796:293–308PubMedGoogle Scholar
  108. 108.
    Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454PubMedCrossRefGoogle Scholar
  109. 109.
    Voulgari A, Pintzas A (2009) Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta 1796:75–90PubMedGoogle Scholar
  110. 110.
    Amente S, Lania L, Majello B (2013) The histone LSD1 demethylase in stemness and cancer transcription programs. Biochim Biophys Acta 1829:981–986PubMedCrossRefGoogle Scholar
  111. 111.
    Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, Liang J, Sun L, Yang X, Shi L et al (2009) LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138:660–672PubMedCrossRefGoogle Scholar
  112. 112.
    Li Q, Shi L, Gui B, Yu W, Wang J, Zhang D, Han X, Yao Z, Shang Y (2011) Binding of the JmjC demethylase JARID1B to LSD1/NuRD suppresses angiogenesis and metastasis in breast cancer cells by repressing chemokine CCL14. Cancer Res 71:6899–6908PubMedCrossRefGoogle Scholar
  113. 113.
    Lin Y, Wu Y, Li J, Dong C, Ye X, Chi YI, Evers BM, Zhou BP (2010) The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J 29:1803–1816PubMedCrossRefGoogle Scholar
  114. 114.
    Li K, Dias SJ, Rimando AM, Dhar S, Mizuno CS, Penman AD, Lewin JR, Levenson AS (2013) Pterostilbene acts through metastasis-associated protein 1 to inhibit tumor growth, progression and metastasis in prostate cancer. PLoS One 8:e57542PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Quintela-Fandino M, Arpaia E, Brenner D, Goh T, Yeung FA, Blaser H, Alexandrova R, Lind EF, Tusche MW, Wakeham A et al (2010) HUNK suppresses metastasis of basal type breast cancers by disrupting the interaction between PP2A and cofilin-1. Proc Natl Acad Sci U S A 107:2622–2627PubMedCentralPubMedCrossRefGoogle Scholar
  116. 116.
    Wertheim GB, Yang TW, Pan TC, Ramne A, Liu Z, Gardner HP, Dugan KD, Kristel P, Kreike B, van de Vijver MJ et al (2009) The Snf1-related kinase, Hunk, is essential for mammary tumor metastasis. Proc Natl Acad Sci U S A 106:15855–15860PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massague J (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451:147–152PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Hurst DR, Edmonds MD, Welch DR (2009) Metastamir: the field of metastasis-regulatory microRNA is spreading. Cancer Res 69:7495–7498PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Ohta S, Lai EW, Pang AL, Brouwers FM, Chan WY, Eisenhofer G, de Krijger R, Ksinantova L, Breza J, Blazicek P et al (2005) Downregulation of metastasis suppressor genes in malignant pheochromocytoma. Int J Cancer 114:139–143PubMedCrossRefGoogle Scholar
  120. 120.
    Pulukuri SM, Patibandla S, Patel J, Estes N, Rao JS (2007) Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors. Oncogene 26:5229–5237PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Chambers AF, Matrisian LM (1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89:1260–1270PubMedCrossRefGoogle Scholar
  122. 122.
    Welch DR, Rinker-Schaeffer CW (1999) What defines a useful marker of metastasis in human cancer? J Natl Cancer Inst 91:1351–1353PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Christopher R. Bohl
    • 1
  • Sitaram Harihar
    • 1
  • Warren L. Denning
    • 1
  • Rahul Sharma
    • 1
  • Danny R. Welch
    • 1
    • 2
  1. 1.Department of Cancer BiologyThe University of Kansas Medical CenterKansas CityUSA
  2. 2.University of Kansas Cancer Center and National Foundation for Cancer Research—Center for Metastasis ResearchThe University of Kansas Cancer CenterKansas CityUSA

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