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Genetics of breast cancer bone metastasis: a sequential multistep pattern

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Abstract

Bone metastasis accounts for the vast majority of breast cancer (BC) metastases, and is related to a high rate of morbidity and mortality. A number of seminal studies have uncovered gene expression signatures involved in BC development and bone metastasis; each of them points at a distinct step of the ‘invasion-metastasis cascade’. In this review, we provide most recently discovered functions of sets of genes that are selected from widely accepted gene signatures that are implicate in BC progression and bone metastasis. We propose a possible sequential pattern of gene expression that may lead a benign primary breast tumor to get aggressiveness and progress toward bone metastasis. A panel of genes which primarily deal with features like DNA replication, survival, proliferation, then, angiogenesis, migration, and invasion has been identified. TGF-β, FGF, NFκB, WNT, PI3K, and JAK-STAT signaling pathways, as the key pathways involved in breast cancer development and metastasis, are evidently regulated by several genes in all three signatures. Epithelial to mesenchymal transition that is also an important mechanism in cancer stem cell generation and metastasis is evidently regulated by these genes. This review provides a comprehensive insight regarding breast cancer bone metastasis that may lead to a better understanding of the disease and take step toward better treatments.

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References

  1. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    CAS  PubMed  Google Scholar 

  2. Siegel R, Naishadham D (2013) Jemal A (2013) Cancer statistics. CA Cancer J Clin 63(1):11–30

    PubMed  Google Scholar 

  3. Mundy GR (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2(8):584–593

    CAS  PubMed  Google Scholar 

  4. Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 350(16):1655–1664

    CAS  PubMed  Google Scholar 

  5. Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147(2):275–292

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Ma XJ et al (2003) Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci USA 100(10):5974–5979

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Yu M et al (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339(6119):580–584

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–1564

    CAS  PubMed  Google Scholar 

  9. Shackleton M et al (2009) Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138(5):822–829

    CAS  PubMed  Google Scholar 

  10. Greaves M, Maley CC (2012) Clonal evolution in cancer. Nature 481(7381):306–313

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Brabletz T et al (2005) Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer 5(9):744–749

    CAS  PubMed  Google Scholar 

  12. Charafe-Jauffret E et al (2009) Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69(4):1302–1313

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Jordan CT, Guzman ML, Noble M (2006) Cancer stem cells. N Engl J Med 355(12):1253–1261

    CAS  PubMed  Google Scholar 

  14. van ‘t Veer LJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536

    Google Scholar 

  15. Kang Y et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3(6):537–549

    CAS  PubMed  Google Scholar 

  16. Smid M et al (2006) Genes associated with breast cancer metastatic to bone. J Clin Oncol Off J Am Soc Clin Oncol 24(15):2261–2267

    CAS  Google Scholar 

  17. Glas AM et al (2006) Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genom 7:278

    Google Scholar 

  18. van’t Veer LJ, Bernards R (2008) Enabling personalized cancer medicine through analysis of gene-expression patterns. Nature 452(7187):564–570

    Google Scholar 

  19. Perou CM et al (1999) Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci USA 96(16):9212–9217

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Perou CM et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752

    CAS  PubMed  Google Scholar 

  21. Zajchowski DA et al (2001) Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res 61(13):5168–5178

    CAS  PubMed  Google Scholar 

  22. Sorlie T et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874

    CAS  PubMed Central  PubMed  Google Scholar 

  23. West M et al (2001) Predicting the clinical status of human breast cancer by using gene expression profiles. Proc Natl Acad Sci USA 98(20):11462–11467

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Grana X, Reddy EP (1995) Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene 11(2):211–219

    CAS  PubMed  Google Scholar 

  25. Ohtani K et al (1999) Cell growth-regulated expression of mammalian MCM5 and MCM6 genes mediated by the transcription factor E2F. Oncogene 18(14):2299–2309

    CAS  PubMed  Google Scholar 

  26. Mehdipour P et al (2009) Prognostic implication of CDC25A and cyclin E expression on primary breast cancer patients. Cell Biol Int 33(10):1050–1056

    CAS  PubMed  Google Scholar 

  27. Liu JH et al (1999) Functional association of TGF-beta receptor II with cyclin B. Oncogene 18(1):269–275

    CAS  PubMed  Google Scholar 

  28. Wottawa M et al (2013) Knockdown of prolyl-4-hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA-MB-231 cells by affecting TGF-beta1 processing. Int J Cancer J Int Cancer 132(12):2787–2798

    CAS  Google Scholar 

  29. Petrella BL, Armstrong DA, Vincenti MP (2012) Interleukin-1 beta and transforming growth factor-beta 3 cooperate to activate matrix metalloproteinase expression and invasiveness in A549 lung adenocarcinoma cells. Cancer Lett 325(2):220–226

    CAS  PubMed  Google Scholar 

  30. Malanchi I et al (2012) Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481(7379):85–89

    CAS  Google Scholar 

  31. Kang YH et al (2012) ESM-1 regulates cell growth and metastatic process through activation of NF-kappaB in colorectal cancer. Cell Signal 24(10):1940–1949

    CAS  PubMed  Google Scholar 

  32. Sonvilla G et al (2008) FGF18 in colorectal tumour cells: autocrine and paracrine effects. Carcinogenesis 29(1):15–24

    CAS  PubMed  Google Scholar 

  33. Hou CH et al (2011) WISP-1 increases MMP-2 expression and cell motility in human chondrosarcoma cells. Biochem Pharmacol 81(11):1286–1295

    CAS  PubMed  Google Scholar 

  34. Dubik D, Dembinski TC, Shiu RP (1987) Stimulation of c-myc oncogene expression associated with estrogen-induced proliferation of human breast cancer cells. Cancer Res 47 24(Pt 1): 6517-21

    Google Scholar 

  35. Watson PH, Pon RT, Shiu RP (1991) Inhibition of c-myc expression by phosphorothioate antisense oligonucleotide identifies a critical role for c-myc in the growth of human breast cancer. Cancer Res 51(15):3996–4000

    CAS  PubMed  Google Scholar 

  36. McEwan MV, Eccles MR, Horsfield JA (2012) Cohesin is required for activation of MYC by estradiol. PLoS ONE 7(11):e49160

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Wu W et al (1998) Overexpression of cdc25A and cdc25B is frequent in primary non-small cell lung cancer but is not associated with overexpression of c-myc. Cancer Res 58(18):4082–4085

    CAS  PubMed  Google Scholar 

  38. Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14(6):818–829

    CAS  PubMed  Google Scholar 

  39. Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25(1):9–34

    CAS  PubMed  Google Scholar 

  40. Orlichenko LS, Radisky DC (2008) Matrix metalloproteinases stimulate epithelial-mesenchymal transition during tumor development. Clin Exp Metastasis 25(6):593–600

    CAS  PubMed  Google Scholar 

  41. Yang AD et al (2006) Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res 66(1):46–51

    CAS  PubMed  Google Scholar 

  42. Mani SA et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Kaplan RN et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Jung Y et al (2009) Expression of PGK1 by prostate cancer cells induces bone formation. Mol Cancer Res MCR 7(10):1595–1604

    CAS  Google Scholar 

  45. Wang J et al (2007) A glycolytic mechanism regulating an angiogenic switch in prostate cancer. Cancer Res 67(1):149–159

    CAS  PubMed  Google Scholar 

  46. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    CAS  PubMed  Google Scholar 

  47. Tian S et al (2010) Biological functions of the genes in the mammaprint breast cancer profile reflect the hallmarks of cancer. Biomark Insights 5:129–138

    PubMed Central  PubMed  Google Scholar 

  48. DeBerardinis RJ et al (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7(1):11–20

    CAS  PubMed  Google Scholar 

  49. Jones RG, Thompson CB (2009) Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev 23(5):537–548

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Thomas DA, Massague J (2005) TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8(5):369–380

    CAS  PubMed  Google Scholar 

  51. Buache E et al (2011) Deficiency in trefoil factor 1 (TFF1) increases tumorigenicity of human breast cancer cells and mammary tumor development in TFF1-knockout mice. Oncogene 30(29):3261–3273

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Emami S et al (2001) Induction of scattering and cellular invasion by trefoil peptides in src- and RhoA-transformed kidney and colonic epithelial cells. FASEB J: official publication of the Federation of American Societies for Experimental Biology 15(2):351–361

    CAS  Google Scholar 

  53. Prest SJ, May FE, Westley BR (2002) The estrogen-regulated protein, TFF1, stimulates migration of human breast cancer cells. FASEB J: official publication of the Federation of American Societies for Experimental Biology 16(6):592–594

    CAS  Google Scholar 

  54. Rodrigues S et al (2003) Trefoil peptides as proangiogenic factors in vivo and in vitro: implication of cyclooxygenase-2 and EGF receptor signaling. FASEB J: official publication of the Federation of American Societies for Experimental Biology 17(1):7–16

    CAS  Google Scholar 

  55. Guleng B et al (2012) TFF3 mediated induction of VEGF via hypoxia in human gastric cancer SGC-7901 cells. Mol Biol Rep 39(4):4127–4134

    CAS  PubMed  Google Scholar 

  56. Blanco MJ et al (2002) Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21(20):3241–3246

    CAS  PubMed  Google Scholar 

  57. Nieto MA (2002) The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3(3):155–166

    CAS  PubMed  Google Scholar 

  58. De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13(2):97–110

    PubMed  Google Scholar 

  59. Liu R et al (2009) KLF5 promotes breast cell survival partially through fibroblast growth factor-binding protein 1-pERK-mediated dual specificity MKP-1 protein phosphorylation and stabilization. J Biol Chem 284(25):16791–16798

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Harris LG et al (2012) Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61. Oncogene 31(28):3370–3380

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Harris LG, Samant RS, Shevde LA (2011) Hedgehog signaling: networking to nurture a promalignant tumor microenvironment. Mol Cancer Res MCR 9(9):1165–1174

    CAS  Google Scholar 

  62. Storz P et al (2009) FOXO3a promotes tumor cell invasion through the induction of matrix metalloproteinases. Mol Cell Biol 29(18):4906–4917

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Lin YC et al (2011) Domain and functional analysis of a novel breast tumor suppressor protein, SCUBE2. J Biol Chem 286(30):27039–27047

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Casimiro S et al (2012) Analysis of a bone metastasis gene expression signature in patients with bone metastasis from solid tumors. Clin Exp Metastasis 29(2):155–164

    CAS  PubMed  Google Scholar 

  65. Guo X, Jose PA, Chen SY (2011) Response gene to complement 32 interacts with Smad3 to promote epithelial-mesenchymal transition of human renal tubular cells. Am J Physiol Cell Physiol 300(6):C1415–C1421

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Epstein RJ (2004) The CXCL12-CXCR4 chemotactic pathway as a target of adjuvant breast cancer therapies. Nat Rev Cancer 4(11):901–909

    CAS  PubMed  Google Scholar 

  67. Zhang XH et al (2009) Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16(1):67–78

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Mikami F et al (2006) The transforming growth factor-beta-Smad3/4 signaling pathway acts as a positive regulator for TLR2 induction by bacteria via a dual mechanism involving functional cooperation with NF-kappaB and MAPK phosphatase 1-dependent negative cross-talk with p38 MAPK. J Biol Chem 281(31):22397–22408

    CAS  PubMed  Google Scholar 

  69. Huang WY et al (2009) RGC-32 mediates transforming growth factor-beta-induced epithelial-mesenchymal transition in human renal proximal tubular cells. J Biol Chem 284(14):9426–9432

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Fitzgerald AM et al (2012) The effects of transforming growth factor-beta2 on the expression of follistatin and activin A in normal and glaucomatous human trabecular meshwork cells and tissues. Invest Ophthalmol Vis Sci 53(11):7358–7369

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Parada C, et al (2013) CTGF mediates Smad-dependent TGFbeta signaling to regulate mesenchymal cell proliferation during palate development. Mol Cell Biol 33(17):3482–3493

    Google Scholar 

  72. Chu CY, et al (2013) Induction of chemokine receptor CXCR4 expression by transforming growth factor-beta1 in human basal cell carcinoma cells. J Dermatol Sci 72(2):123–133

    Google Scholar 

  73. Bertran E, et al (2013) Overactivation of the TGF-beta pathway confers a mesenchymal-like phenotype and CXCR4-dependent migratory properties to liver tumor cells. Hepatology 58(6):2032–2044

    Google Scholar 

  74. Gupta J et al (2011) TGFbeta-dependent induction of interleukin-11 and interleukin-8 involves SMAD and p38 MAPK pathways in breast tumor models with varied bone metastases potential. Cancer Biol Ther 11(3):311–316

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Calon A et al (2012) Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell 22(5):571–584

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Vu TH, Werb Z (2000) Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev 14(17):2123–2133

    CAS  PubMed  Google Scholar 

  77. Winbanks CE et al (2012) Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. J Cell Biol 197(7):997–1008

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Kornmann M et al (1997) Fibroblast growth factor-5 stimulates mitogenic signaling and is overexpressed in human pancreatic cancer: evidence for autocrine and paracrine actions. Oncogene 15(12):1417–1424

    CAS  PubMed  Google Scholar 

  79. Tan TW et al (2009) CTGF enhances migration and MMP-13 up-regulation via alphavbeta3 integrin, FAK, ERK, and NF-kappaB-dependent pathway in human chondrosarcoma cells. J Cell Biochem 107(2):345–356

    CAS  PubMed  Google Scholar 

  80. Shimo T et al (2006) Pathogenic role of connective tissue growth factor (CTGF/CCN2) in osteolytic metastasis of breast cancer. J Bone Miner Res Off J Am Soc Bone Miner Res 21(7):1045–1059

    CAS  Google Scholar 

  81. Lu X et al (2009) ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis. Genes Dev 23(16):1882–1894

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Muller A et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56

    CAS  PubMed  Google Scholar 

  83. McCoy EM et al (2013) IL-11 produced by breast cancer cells augments osteoclastogenesis by sustaining the pool of osteoclast progenitor cells. BMC Cancer 13:16

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Gao YB et al (2013) Enhanced production of CTGF and IL-11 from highly metastatic hepatoma cells under hypoxic conditions: an implication of hepatocellular carcinoma metastasis to bone. J Cancer Res Clin Oncol 139(4):669–679

    CAS  PubMed  Google Scholar 

  85. Ren L et al (2013) Bone metastasis from breast cancer involves elevated IL-11 expression and the gp130/STAT3 pathway. Med Oncol 30(3):634

    PubMed  Google Scholar 

  86. Jing Y et al (2011) Epithelial-mesenchymal transition in tumor microenvironment. Cell Biosci 1:29

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Fazilaty H et al (2013) Crosstalk between breast cancer stem cells and metastatic niche: emerging molecular metastasis pathway? Tumour Biol J Int Soc Oncodev Biol Med 34(4):2019–2030

    CAS  Google Scholar 

  88. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Investig 119(6):1420–1428

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Deckers M et al (2006) The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res 66(4):2202–2209

    CAS  PubMed  Google Scholar 

  90. Kaimori A et al (2007) Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem 282(30):22089–22101

    CAS  PubMed  Google Scholar 

  91. Ashcroft GS et al (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1(5):260–266

    CAS  PubMed  Google Scholar 

  92. Xu J, Lamouille S, Derynck R (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res 19(2):156–172

    CAS  PubMed  Google Scholar 

  93. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425(6958):577–584

    CAS  PubMed  Google Scholar 

  94. Byun HJ et al (2006) A splice variant of CD99 increases motility and MMP-9 expression of human breast cancer cells through the AKT-, ERK-, and JNK-dependent AP-1 activation signaling pathways. J Biol Chem 281(46):34833–34847

    CAS  PubMed  Google Scholar 

  95. Dang H et al (2011) Snail1 induces epithelial-to-mesenchymal transition and tumor initiating stem cell characteristics. BMC Cancer 11:396

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Ciruna B, Rossant J (2001) FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev Cell 1(1):37–49

    CAS  PubMed  Google Scholar 

  97. Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10(2):116–129

    CAS  PubMed  Google Scholar 

  98. Min C et al (2008) NF-kappaB and epithelial to mesenchymal transition of cancer. J Cell Biochem 104(3):733–744

    CAS  PubMed  Google Scholar 

  99. Julien S et al (2007) Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene 26(53):7445–7456

    CAS  PubMed  Google Scholar 

  100. Huber MA et al (2004) NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Investig 114(4):569–581

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Maier HJ et al (2010) NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett 295(2):214–228

    CAS  PubMed  Google Scholar 

  102. Velasco-Velazquez MA et al (2012) Breast cancer stem cells. Int J Biochem Cell Biol 44(4):573–577

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Malanchi I et al (2008) Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature 452(7187):650–653

    CAS  PubMed  Google Scholar 

  104. Scheel C et al (2011) Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145(6):926–940

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Larue L, Bellacosa A (2005) Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 24(50):7443–7454

    CAS  PubMed  Google Scholar 

  106. Muraoka-Cook RS, Dumont N, Arteaga CL (2005) Dual role of transforming growth factor beta in mammary tumorigenesis and metastatic progression. Clin Cancer Res Off J Am Assoc Cancer Res 11(2 Pt 2):937s–943s

    CAS  Google Scholar 

  107. Marotta LL et al (2011) The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(-) stem cell-like breast cancer cells in human tumors. J Clin Investig 121(7):2723–2735

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Niu G et al (2002) Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene 21(46):7001–7010

    CAS  PubMed  Google Scholar 

  109. Bowman T et al (2000) STATs in oncogenesis. Oncogene 19(21):2474–2488

    CAS  PubMed  Google Scholar 

  110. Quintas-Cardama A, Verstovsek S (2013) Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin Cancer Res Off J Am Assoc Cancer Res 19(8):1933–1940

    CAS  Google Scholar 

  111. Lu X, Kang Y (2010) Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res Off J Am Assoc Cancer Res 16(24):5928–5935

    CAS  Google Scholar 

  112. Brabletz T (2012) To differentiate or not–routes towards metastasis. Nat Rev Cancer 12(6):425–436

    CAS  PubMed  Google Scholar 

  113. Lu X et al (2011) VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell 20(6):701–714

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Chen Q, Massague J (2012) Molecular pathways: VCAM-1 as a potential therapeutic target in metastasis. Clin Cancer Res Off J Am Assoc Cancer Res 18(20):5520–5525

    CAS  Google Scholar 

  115. Chen Q, Zhang XH, Massague J (2011) Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20(4):538–549

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Boyce BF, Xing L (2007) Biology of RANK, RANKL, and osteoprotegerin. Arthr Res Ther 9(Suppl 1):S1

    Google Scholar 

  117. Jones DH et al (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440(7084):692–696

    CAS  PubMed  Google Scholar 

  118. Casimiro S et al (2013) RANKL/RANK/MMP-1 molecular triad contributes to the metastatic phenotype of breast and prostate cancer cells in vitro. PLoS ONE 8(5):e63153

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Park HR et al (2003) Expression of osteoprotegerin and RANK ligand in breast cancer bone metastasis. J Korean Med Sci 18(4):541–546

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Peng X et al (2013) Differential expression of the RANKL/RANK/OPG system is associated with bone metastasis in human non-small cell lung cancer. PLoS ONE 8(3):e58361

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Palafox M et al (2012) RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res 72(11):2879–2888

    CAS  PubMed  Google Scholar 

  122. Yin JJ et al (1999) TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Investig 103(2):197–206

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Liang Y et al (2012) Transcriptional network analysis identifies BACH1 as a master regulator of breast cancer bone metastasis. J Biol Chem 287(40):33533–33544

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Okita Y et al (2013) Transforming growth factor-beta induces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene. J Biol Chem 288(28):20658–20667

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Shubbar E et al (2013) Elevated cyclin B2 expression in invasive breast carcinoma is associated with unfavorable clinical outcome. BMC Cancer 13:1

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Caldon CE et al (2012) Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther 11(7):1488–1499

    CAS  PubMed  Google Scholar 

  127. Payton M et al (2002) Deregulation of cyclin E2 expression and associated kinase activity in primary breast tumors. Oncogene 21(55):8529–8534

    CAS  PubMed  Google Scholar 

  128. Epping MT et al (2011) TSPYL5 suppresses p53 levels and function by physical interaction with USP7. Nat Cell Biol 13(1):102–108

    CAS  PubMed  Google Scholar 

  129. Kim EJ et al (2010) TSPYL5 is involved in cell growth and the resistance to radiation in A549 cells via the regulation of p21(WAF1/Cip1) and PTEN/AKT pathway. Biochem Biophys Res Commun 392(3):448–453

    CAS  PubMed  Google Scholar 

  130. Gulzar ZG, McKenney JK, Brooks JD (2013) Increased expression of NuSAP in recurrent prostate cancer is mediated by E2F1. Oncogene 32(1):70–77

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Chou HY et al (2011) Phosphorylation of NuSAP by Cdk1 regulates its interaction with microtubules in mitosis. Cell Cycle 10(23):4083–4089

    CAS  PubMed  Google Scholar 

  132. Raemaekers T et al (2003) NuSAP, a novel microtubule-associated protein involved in mitotic spindle organization. J Cell Biol 162(6):1017–1029

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Horn D et al (2010) The conserved mitochondrial twin Cx9C protein Cmc2 Is a Cmc1 homologue essential for cytochrome c oxidase biogenesis. J Biol Chem 285(20):15088–15099

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Xu J et al (2013) MiR-223/Ect2/p21 signaling regulates osteosarcoma cell cycle progression and proliferation. Biomed Pharmacother 67(5):381–386

    CAS  PubMed  Google Scholar 

  135. Weeks A et al (2012) ECT2 and RASAL2 mediate mesenchymal-amoeboid transition in human astrocytoma cells. Am J Pathol 181(2):662–674

    CAS  PubMed  Google Scholar 

  136. Cook DR et al (2011) The ect2 rho Guanine nucleotide exchange factor is essential for early mouse development and normal cell cytokinesis and migration. Genes Cancer 2(10):932–942

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Thomae AW et al (2011) Different roles of the human Orc6 protein in the replication initiation process. Cell Mol Life Sci CMLS 68(22):3741–3756

    CAS  Google Scholar 

  138. Ueki T et al (2008) Involvement of elevated expression of multiple cell-cycle regulator, DTL/RAMP (denticleless/RA-regulated nuclear matrix associated protein), in the growth of breast cancer cells. Oncogene 27(43):5672–5683

    CAS  PubMed  Google Scholar 

  139. Pan HW et al (2006) Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma. Cell Cycle 5(22):2676–2687

    CAS  PubMed  Google Scholar 

  140. Liu CL et al (2007) L2dtl is essential for cell survival and nuclear division in early mouse embryonic development. J Biol Chem 282(2):1109–1118

    CAS  PubMed  Google Scholar 

  141. Mollinari C et al (2002) PRC1 is a microtubule binding and bundling protein essential to maintain the mitotic spindle midzone. J Cell Biol 157(7):1175–1186

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Joshi K et al (2013) MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells. Stem Cells 31(6):1051–1063

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Gu C et al (2013) Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner. Stem Cells 31(5):870–881

    CAS  PubMed  Google Scholar 

  144. Lin ML et al (2007) Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of the Bcl-2 family. Breast Cancer Res BCR 9(1):R17

    Google Scholar 

  145. Nakano I et al (2008) Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. J Neurosci Res 86(1):48–60

    CAS  PubMed  Google Scholar 

  146. Peurala E et al (2012) Expressions of individual PHDs associate with good prognostic factors and increased proliferation in breast cancer patients. Breast Cancer Res Treat 133(1):179–188

    CAS  PubMed  Google Scholar 

  147. Metzen E et al (2005) Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element. Biochem J 387(Pt 3):711–717

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Chan DA et al (2009) Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer Cell 15(6):527–538

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Mak P et al (2013) Estrogen receptor beta sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription. Proc Natl Acad Sci USA 110(12):4708–4713

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Flavahan WA et al (2013) Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat Neurosci 16(10):1373–1382

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Mimura I et al (2012) Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. Mol Cell Biol 32(15):3018–3032

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Sureshbabu A et al (2012) IGFBP5 induces cell adhesion, increases cell survival and inhibits cell migration in MCF-7 human breast cancer cells. J Cell Sci 125(Pt 7):1693–1705

    CAS  PubMed  Google Scholar 

  153. Clark GJ, Der CJ (1995) Aberrant function of the Ras signal transduction pathway in human breast cancer. Breast Cancer Res Treat 35(1):133–144

    CAS  PubMed  Google Scholar 

  154. Aitkenhead M et al (2002) Identification of endothelial cell genes expressed in an in vitro model of angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM. Microvasc Res 63(2):159–171

    CAS  PubMed  Google Scholar 

  155. Sonoda E et al (2001) Scc1/Rad21/Mcd1 is required for sister chromatid cohesion and kinetochore function in vertebrate cells. Dev Cell 1(6):759–770

    CAS  PubMed  Google Scholar 

  156. Birkenbihl RP, Subramani S (1992) Cloning and characterization of rad21 an essential gene of Schizosaccharomyces pombe involved in DNA double-strand-break repair. Nucleic Acids Res 20(24):6605–6611

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Wu G et al (2003) DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development. Cancer Res 63(10):2351–2357

    CAS  PubMed  Google Scholar 

  158. Lammer C et al (1998) The cdc25B phosphatase is essential for the G2/M phase transition in human cells. J Cell Sci 111(Pt 16):2445–2453

    CAS  PubMed  Google Scholar 

  159. Li Y et al (2011) ShRNA-targeted centromere protein A inhibits hepatocellular carcinoma growth. PLoS ONE 6(3):e17794

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Tomonaga T et al (2003) Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer. Cancer Res 63(13):3511–3516

    CAS  PubMed  Google Scholar 

  161. Shashni B et al (2013) Glycolytic enzymes PGK1 and PKM2 as novel transcriptional targets of PPARgamma in breast cancer pathophysiology. J Drug Target 21(2):161–174

    CAS  PubMed  Google Scholar 

  162. Fang G, Yu H, Kirschner MW (1998) The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev 12(12):1871–1883

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Sotillo R et al (2007) Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11(1):9–23

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Lan Y et al (2008) Aberrant expression of Cks1 and Cks2 contributes to prostate tumorigenesis by promoting proliferation and inhibiting programmed cell death. Int J Cancer J Int Cancer 123(3):543–551

    CAS  Google Scholar 

  165. Kang MA et al (2009) Upregulation of the cycline kinase subunit CKS2 increases cell proliferation rate in gastric cancer. J Cancer Res Clin Oncol 135(6):761–769

    CAS  PubMed  Google Scholar 

  166. Johnson VL et al (2004) Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression. J Cell Sci 117(Pt 8):1577–1589

    CAS  PubMed  Google Scholar 

  167. Grabsch H et al (2003) Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer: association with tumour cell proliferation. J Pathol 200(1):16–22

    CAS  PubMed  Google Scholar 

  168. Waltenberger J et al (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269(43):26988–26995

    CAS  PubMed  Google Scholar 

  169. Yoshiji H et al (1996) Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res 56(9):2013–2016

    CAS  PubMed  Google Scholar 

  170. Huegel J et al (2013) Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in Hereditary Multiple Exostoses. Dev Biol 377(1):100–112

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Wang Y et al (2013) Involvement of Ext1 and heparanase in migration of mouse FBJ osteosarcoma cells. Mol Cell Biochem 373(1–2):63–72

    CAS  PubMed  Google Scholar 

  172. Hager MH et al (2012) DIAPH3 governs the cellular transition to the amoeboid tumour phenotype. EMBO Mol Med 4(8):743–760

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Gupton SL et al (2007) mDia2 regulates actin and focal adhesion dynamics and organization in the lamella for efficient epithelial cell migration. J Cell Sci 120(Pt 19):3475–3487

    CAS  PubMed  Google Scholar 

  174. Block J et al (2008) Filopodia formation induced by active mDia2/Drf3. J Microsc 231(3):506–517

    CAS  PubMed  Google Scholar 

  175. Wilkinson S, Paterson HF, Marshall CJ (2005) Cdc42-MRCK and Rho-ROCK signalling cooperate in myosin phosphorylation and cell invasion. Nat Cell Biol 7(3):255–261

    CAS  PubMed  Google Scholar 

  176. Balasenthil S et al (2011) A migration signature and plasma biomarker panel for pancreatic adenocarcinoma. Cancer Prev Res (Phila) 4(1):137–149

    CAS  Google Scholar 

  177. Barkefors I et al (2011) Exocyst complex component 3-like 2 (EXOC3L2) associates with the exocyst complex and mediates directional migration of endothelial cells. J Biol Chem 286(27):24189–24199

    CAS  PubMed Central  PubMed  Google Scholar 

  178. Liu J et al (2012) Exo70 stimulates the Arp2/3 complex for lamellipodia formation and directional cell migration. Curr Biol CB 22(16):1510–1515

    CAS  Google Scholar 

  179. Wu Y et al (2007) Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia. Oncogene 26(5):765–773

    CAS  PubMed  Google Scholar 

  180. Ketterer K et al (2009) Neuromedin U is overexpressed in pancreatic cancer and increases invasiveness via the hepatocyte growth factor c-Met pathway. Cancer Lett 277(1):72–81

    CAS  PubMed  Google Scholar 

  181. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676

    CAS  PubMed  Google Scholar 

  182. Gerhardt H et al (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161(6):1163–1177

    CAS  PubMed Central  PubMed  Google Scholar 

  183. Skobe M et al (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7(2):192–198

    CAS  PubMed  Google Scholar 

  184. Hiratsuka S et al (2002) MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2(4):289–300

    CAS  PubMed  Google Scholar 

  185. Belotti D et al (2003) Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: implications for ascites formation. Cancer Res 63(17):5224–5229

    CAS  PubMed  Google Scholar 

  186. Gauglhofer C et al (2011) Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. Hepatology 53(3):854–864

    CAS  PubMed  Google Scholar 

  187. Wei W et al (2013) FGF18 as a prognostic and therapeutic biomarker in ovarian cancer. J Clin Investig 123(10):4435–4448

    CAS  PubMed Central  PubMed  Google Scholar 

  188. Xu L et al (2000) WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene. Genes Dev 14(5):585–595

    CAS  PubMed Central  PubMed  Google Scholar 

  189. Su F et al (2002) WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase. Genes Dev 16(1):46–57

    CAS  PubMed Central  PubMed  Google Scholar 

  190. Liu JF et al (2013) CCN4 induces vascular cell adhesion molecule-1 expression in human synovial fibroblasts and promotes monocyte adhesion. Biochim Biophys Acta 1833(5):966–975

    CAS  PubMed  Google Scholar 

  191. Inkson CA et al (2008) TGF-beta1 and WISP-1/CCN-4 can regulate each other’s activity to cooperatively control osteoblast function. J Cell Biochem 104(5):1865–1878

    CAS  PubMed Central  PubMed  Google Scholar 

  192. Ono M et al (2013) WISP1/CCN4: a potential target for inhibiting prostate cancer growth and spread to bone. PLoS ONE 8(8):e71709

    CAS  PubMed Central  PubMed  Google Scholar 

  193. Nishi H et al (2004) Hypoxia-inducible factor-1 transactivates transforming growth factor-beta3 in trophoblast. Endocrinology 145(9):4113–4118

    CAS  PubMed  Google Scholar 

  194. Medici D, Hay ED, Olsen BR (2008) Snail and Slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3. Mol Biol Cell 19(11):4875–4887

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Nguyen AV, Pollard JW (2000) Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution. Development 127(14):3107–3118

    CAS  PubMed  Google Scholar 

  196. Amiry N et al (2009) Trefoil factor-1 (TFF1) enhances oncogenicity of mammary carcinoma cells. Endocrinology 150(10):4473–4483

    CAS  PubMed  Google Scholar 

  197. Katoh M (2003) Trefoil factors and human gastric cancer (review). Int J Mol Med 12(1):3–9

    CAS  PubMed  Google Scholar 

  198. Ahmed AR et al (2012) TFF3 is a normal breast epithelial protein and is associated with differentiated phenotype in early breast cancer but predisposes to invasion and metastasis in advanced disease. Am J Pathol 180(3):904–916

    PubMed  Google Scholar 

  199. Wang Z, Hao Y, Lowe AW (2008) The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer Res 68(2):492–497

    CAS  PubMed  Google Scholar 

  200. Hrstka R et al (2010) The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers. Oncogene 29(34):4838–4847

    CAS  PubMed  Google Scholar 

  201. Innes HE et al (2006) Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients. Br J Cancer 94(7):1057–1065

    CAS  PubMed Central  PubMed  Google Scholar 

  202. Park SW et al (2009) The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proc Natl Acad Sci USA 106(17):6950–6955

    CAS  PubMed Central  PubMed  Google Scholar 

  203. Tiang JM, Butcher NJ, Minchin RF (2010) Small molecule inhibition of arylamine N-acetyltransferase Type I inhibits proliferation and invasiveness of MDA-MB-231 breast cancer cells. Biochem Biophys Res Commun 393(1):95–100

    CAS  PubMed  Google Scholar 

  204. Tiang JM et al (2011) RNAi-mediated knock-down of arylamine N-acetyltransferase-1 expression induces E-cadherin up-regulation and cell–cell contact growth inhibition. PLoS ONE 6(2):e17031

    CAS  PubMed Central  PubMed  Google Scholar 

  205. Lanningham-Foster L et al (2002) Overexpression of CRIP in transgenic mice alters cytokine patterns and the immune response. Am J Physiol Endocrinol Metab 282(6):E1197–E1203

    CAS  PubMed  Google Scholar 

  206. Nobes CD et al (1998) A new member of the Rho family, Rnd1, promotes disassembly of actin filament structures and loss of cell adhesion. J Cell Biol 141(1):187–197

    CAS  PubMed Central  PubMed  Google Scholar 

  207. Wang GL et al (2012) The effect of NET-1 on the proliferation, migration and endocytosis of the SMMC-7721 HCC cell line. Oncol Rep 27(6):1944–1952

    CAS  PubMed  Google Scholar 

  208. Chen L et al (2010) Suppression of TSPAN1 by RNA interference inhibits proliferation and invasion of colon cancer cells in vitro. Tumori 96(5):744–750

    CAS  PubMed  Google Scholar 

  209. Cheng CJ et al (2009) SCUBE2 suppresses breast tumor cell proliferation and confers a favorable prognosis in invasive breast cancer. Cancer Res 69(8):3634–3641

    CAS  PubMed  Google Scholar 

  210. Tsai MT et al (2009) Isolation and characterization of a secreted, cell-surface glycoprotein SCUBE2 from humans. Biochem J 422(1):119–128

    CAS  PubMed  Google Scholar 

  211. Ilantzis C et al (2002) Deregulated expression of the human tumor marker CEA and CEA family member CEACAM6 disrupts tissue architecture and blocks colonocyte differentiation. Neoplasia 4(2):151–163

    CAS  PubMed Central  PubMed  Google Scholar 

  212. Duxbury MS et al (2004) CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells. Oncogene 23(2):465–473

    CAS  PubMed  Google Scholar 

  213. Elmarghani A, Abuabaid H, Kjellen P (2009) TOM1L is involved in a novel signaling pathway important for the IL-2 production in Jurkat T cells stimulated by CD3/CD28 co-ligation. Mediators Inflamm 2009:416298

    PubMed Central  PubMed  Google Scholar 

  214. Liu NS et al (2009) Participation of Tom1L1 in EGF-stimulated endocytosis of EGF receptor. The EMBO journal 28(22):3485–3499

    CAS  PubMed Central  PubMed  Google Scholar 

  215. Hendrix MJ et al (1996) Role of intermediate filaments in migration, invasion and metastasis. Cancer Metastasis Rev 15(4):507–525

    CAS  PubMed  Google Scholar 

  216. Tassi E et al (2001) Enhancement of fibroblast growth factor (FGF) activity by an FGF-binding protein. J Biol Chem 276(43):40247–40253

    CAS  PubMed  Google Scholar 

  217. Abuharbeid S, Czubayko F, Aigner A (2006) The fibroblast growth factor-binding protein FGF-BP. Int J Biochem Cell Biol 38(9):1463–1468

    CAS  PubMed  Google Scholar 

  218. Medema RH et al (2000) AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404(6779):782–787

    CAS  PubMed  Google Scholar 

  219. Rena G et al (1999) Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem 274(24):17179–17183

    CAS  PubMed  Google Scholar 

  220. Brunet A et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6):857–868

    CAS  PubMed  Google Scholar 

  221. Hu MC et al (2004) IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117(2):225–237

    CAS  PubMed  Google Scholar 

  222. Yang JY et al (2008) ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 10(2):138–148

    CAS  PubMed Central  PubMed  Google Scholar 

  223. Khatri S et al (2010) FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1. J Biol Chem 285(21):15960–15965

    CAS  PubMed Central  PubMed  Google Scholar 

  224. Morelli C et al (2010) Akt2 inhibition enables the forkhead transcription factor FoxO3a to have a repressive role in estrogen receptor alpha transcriptional activity in breast cancer cells. Mol Cell Biol 30(3):857–870

    CAS  PubMed Central  PubMed  Google Scholar 

  225. Zou Y et al (2008) Forkhead box transcription factor FOXO3a suppresses estrogen-dependent breast cancer cell proliferation and tumorigenesis. Breast Cancer Res BCR 10(1):R21

    Google Scholar 

  226. Karadedou CT et al (2012) FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer. Oncogene 31(14):1845–1858

    CAS  PubMed Central  PubMed  Google Scholar 

  227. Cano A et al (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2(2):76–83

    CAS  PubMed  Google Scholar 

  228. Vega S et al (2004) Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 18(10):1131–1143

    CAS  PubMed Central  PubMed  Google Scholar 

  229. Gu YM et al (2008) Elevated thymosin beta15 expression is associated with progression and metastasis of non-small cell lung cancer. APMIS Acta Pathol Microbiol Immunol Scand 116(6):484–490

    CAS  Google Scholar 

  230. Bao L et al (1996) Thymosin beta 15: a novel regulator of tumor cell motility upregulated in metastatic prostate cancer. Nat Med 2(12):1322–1328

    CAS  PubMed  Google Scholar 

  231. Zeng G et al (2012) METCAM/MUC18 augments migration, invasion, and tumorigenicity of human breast cancer SK-BR-3 cells. Gene 492(1):229–238

    CAS  PubMed  Google Scholar 

  232. Zabouo G et al (2009) CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines. Breast Cancer Res BCR 11(1):R1

    Google Scholar 

  233. Jiang T et al (2012) CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. Blood 120(11):2330–2339

    CAS  PubMed  Google Scholar 

  234. Stalin J et al (2013) Soluble melanoma cell adhesion molecule (sMCAM/sCD146) promotes angiogenic effects on endothelial progenitor cells through angiomotin. J Biol Chem 288(13):8991–9000

    CAS  PubMed Central  PubMed  Google Scholar 

  235. Imbert AM et al (2012) CD146 expression in human breast cancer cell lines induces phenotypic and functional changes observed in Epithelial to Mesenchymal Transition. PLoS ONE 7(8):e43752

    CAS  PubMed Central  PubMed  Google Scholar 

  236. Zhang X, et al. (2013) MCAM expression is associated with poor prognosis in non-small cell lung cancer. Clin Transl Oncol. Official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico

  237. Chan DN et al (2012) PTK7 marks the first human developmental EMT in vitro. PLoS ONE 7(11):e50432

    CAS  PubMed Central  PubMed  Google Scholar 

  238. Yen WW et al (2009) PTK7 is essential for polarized cell motility and convergent extension during mouse gastrulation. Development 136(12):2039–2048

    CAS  PubMed Central  PubMed  Google Scholar 

  239. Lu X et al (2004) PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature 430(6995):93–98

    CAS  PubMed  Google Scholar 

  240. Shin WS et al (2008) Soluble PTK7 inhibits tube formation, migration, and invasion of endothelial cells and angiogenesis. Biochem Biophys Res Commun 371(4):793–798

    CAS  PubMed  Google Scholar 

  241. Golubkov VS et al (2010) The Wnt/planar cell polarity protein-tyrosine kinase-7 (PTK7) is a highly efficient proteolytic target of membrane type-1 matrix metalloproteinase: implications in cancer and embryogenesis. J Biol Chem 285(46):35740–35749

    CAS  PubMed Central  PubMed  Google Scholar 

  242. Sun Q, et al. (2013) Overexpression of response gene to complement 32 (RGC32) promotes cell invasion and induces epithelial-mesenchymal transition in lung cancer cells via the NF-kappaB signaling pathway. Tumour Biol J Int Soc Oncodev Biol Med

  243. Sonnylal S et al (2013) Connective tissue growth factor causes EMT-like cell fate changes in vivo and in vitro. J Cell Sci 126(Pt 10):2164–2175

    CAS  PubMed Central  PubMed  Google Scholar 

  244. Muratoglu SC, et al. (2013) LRP1 protects the vasculature by regulating levels of connective tissue growth factor and HtrA1. Arterioscler Thromb Vasc Biol

  245. Kondo S et al (2002) Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases. Carcinogenesis 23(5):769–776

    CAS  PubMed  Google Scholar 

  246. Lau LF, Lam SC (1999) The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res 248(1):44–57

    CAS  PubMed  Google Scholar 

  247. Chen PS et al (2007) CTGF enhances the motility of breast cancer cells via an integrin-alphavbeta3-ERK1/2-dependent S100A4-upregulated pathway. J Cell Sci 120(Pt 12):2053–2065

    CAS  PubMed  Google Scholar 

  248. Hugo HJ et al (2009) Staurosporine augments EGF-mediated EMT in PMC42-LA cells through actin depolymerisation, focal contact size reduction and Snail1 induction: a model for cross-modulation. BMC Cancer 9:235

    PubMed Central  PubMed  Google Scholar 

  249. Basilico C, Moscatelli D (1992) The FGF family of growth factors and oncogenes. Adv Cancer Res 59:115–165

    CAS  PubMed  Google Scholar 

  250. Giordano FJ et al (1996) Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nat Med 2(5):534–539

    CAS  PubMed  Google Scholar 

  251. Allerstorfer S et al (2008) FGF5 as an oncogenic factor in human glioblastoma multiforme: autocrine and paracrine activities. Oncogene 27(30):4180–4190

    CAS  PubMed Central  PubMed  Google Scholar 

  252. Ricciardelli C et al (2011) The ADAMTS1 protease gene is required for mammary tumor growth and metastasis. Am J Pathol 179(6):3075–3085

    CAS  PubMed Central  PubMed  Google Scholar 

  253. Krampert M et al (2005) ADAMTS1 proteinase is up-regulated in wounded skin and regulates migration of fibroblasts and endothelial cells. J Biol Chem 280(25):23844–23852

    CAS  PubMed  Google Scholar 

  254. Esselens C et al (2010) The cleavage of semaphorin 3C induced by ADAMTS1 promotes cell migration. J Biol Chem 285(4):2463–2473

    CAS  PubMed Central  PubMed  Google Scholar 

  255. Su SC et al (2008) Molecular profile of endothelial invasion of three-dimensional collagen matrices: insights into angiogenic sprout induction in wound healing. Am J Physiol Cell Physiol 295(5):C1215–C1229

    CAS  PubMed  Google Scholar 

  256. Luque A, Carpizo DR, Iruela-Arispe ML (2003) ADAMTS1/METH1 inhibits endothelial cell proliferation by direct binding and sequestration of VEGF165. J Biol Chem 278(26):23656–23665

    CAS  PubMed  Google Scholar 

  257. Vazquez F et al (1999) METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity. J Biol Chem 274(33):23349–23357

    CAS  PubMed  Google Scholar 

  258. Kucia M et al (2005) Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis. Stem Cells 23(7):879–894

    CAS  PubMed  Google Scholar 

  259. Teicher BA, Fricker SP (2010) CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res Off J Am Assoc Cancer Res 16(11):2927–2931

    CAS  Google Scholar 

  260. Wang Z et al (2008) Blockade of SDF-1/CXCR4 signalling inhibits pancreatic cancer progression in vitro via inactivation of canonical Wnt pathway. Br J Cancer 99(10):1695–1703

    CAS  PubMed Central  PubMed  Google Scholar 

  261. Mimeault M, Batra SK (2013) Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J Cell Mol Med 17(1):30–54

    CAS  PubMed Central  PubMed  Google Scholar 

  262. Conley-Lacomb MK et al (2013) PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling. Mol Cancer 12(1):85

    CAS  PubMed Central  PubMed  Google Scholar 

  263. Guo D, Huang J, Gong J (2012) Bone morphogenetic protein 4 (BMP4) is required for migration and invasion of breast cancer. Mol Cell Biochem 363(1–2):179–190

    CAS  PubMed  Google Scholar 

  264. Onoue T et al (2006) Epithelial-mesenchymal transition induced by the stromal cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma cells. Int J Oncol 29(5):1133–1138

    CAS  PubMed  Google Scholar 

  265. Jung MJ et al (2013) Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells. Oncogene 32(2):209–221

    CAS  PubMed  Google Scholar 

  266. Li TM et al (2012) Interleukin-11 increases cell motility and up-regulates intercellular adhesion molecule-1 expression in human chondrosarcoma cells. J Cell Biochem 113(11):3353–3362

    CAS  PubMed  Google Scholar 

  267. Yoshizaki A et al (2006) Expression of interleukin (IL)-11 and IL-11 receptor in human colorectal adenocarcinoma: IL-11 up-regulation of the invasive and proliferative activity of human colorectal carcinoma cells. Int J Oncol 29(4):869–876

    CAS  PubMed  Google Scholar 

  268. Nakayama T et al (2007) Expression of interleukin-11 (IL-11) and IL-11 receptor alpha in human gastric carcinoma and IL-11 upregulates the invasive activity of human gastric carcinoma cells. Int J Oncol 30(4):825–833

    CAS  PubMed  Google Scholar 

  269. Shin SY et al (2012) Transcriptional regulation of the interleukin-11 gene by oncogenic Ras. Carcinogenesis 33(12):2467–2476

    CAS  PubMed  Google Scholar 

  270. Foley CJ et al (2012) Matrix metalloprotease-1a promotes tumorigenesis and metastasis. J Biol Chem 287(29):24330–24338

    CAS  PubMed Central  PubMed  Google Scholar 

  271. Gupta GP et al (2007) Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446(7137):765–770

    CAS  PubMed  Google Scholar 

  272. Masckauchan TN et al (2006) Wnt5a signaling induces proliferation and survival of endothelial cells in vitro and expression of MMP-1 and Tie-2. Mol Biol Cell 17(12):5163–5172

    CAS  PubMed Central  PubMed  Google Scholar 

  273. Reunanen N et al (2002) Activation of p38 alpha MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization. J Biol Chem 277(35):32360–32368

    CAS  PubMed  Google Scholar 

  274. Kim MY et al (2009) Tumor self-seeding by circulating cancer cells. Cell 139(7):1315–1326

    PubMed Central  PubMed  Google Scholar 

  275. Lin J et al (2009) Four and a half LIM domains 1 (FHL1) and receptor interacting protein of 140 kDa (RIP140) interact and cooperate in estrogen signaling. Int J Biochem Cell Biol 41(7):1613–1618

    CAS  PubMed  Google Scholar 

  276. Ding L et al (2009) Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway. J Clin Investig 119(2):349–361

    CAS  PubMed Central  PubMed  Google Scholar 

  277. Lin J et al (2012) FHL family members suppress vascular endothelial growth factor expression through blockade of dimerization of HIF1alpha and HIF1beta. IUBMB Life 64(11):921–930

    CAS  PubMed  Google Scholar 

  278. Tong XK, Hamel E (2007) Transforming growth factor-beta 1 impairs endothelin-1-mediated contraction of brain vessels by inducing mitogen-activated protein (MAP) kinase phosphatase-1 and inhibiting p38 MAP kinase. Mol Pharmacol 72(6):1476–1483

    CAS  PubMed  Google Scholar 

  279. Owens DM, Keyse SM (2007) Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26(22):3203–3213

    CAS  PubMed  Google Scholar 

  280. Li M et al (2003) The phosphatase MKP1 is a transcriptional target of p53 involved in cell cycle regulation. J Biol Chem 278(42):41059–41068

    CAS  PubMed  Google Scholar 

  281. Liu YX et al (2008) DUSP1 is controlled by p53 during the cellular response to oxidative stress. Mol Cancer Res MCR 6(4):624–633

    CAS  Google Scholar 

  282. Bellou S et al (2009) VEGF autoregulates its proliferative and migratory ERK1/2 and p38 cascades by enhancing the expression of DUSP1 and DUSP5 phosphatases in endothelial cells. Am J Physiol Cell Physiol 297(6):C1477–C1489

    CAS  PubMed  Google Scholar 

  283. Farabegoli F et al (2005) Suppressor of cytokine signalling 2 (SOCS-2) expression in breast carcinoma. J Clin Pathol 58(10):1046–1050

    CAS  PubMed Central  PubMed  Google Scholar 

  284. Harris J et al (2006) Socs2 and elf5 mediate prolactin-induced mammary gland development. Mol Endocrinol 20(5):1177–1187

    CAS  PubMed  Google Scholar 

  285. Tannahill GM et al (2005) SOCS2 can enhance interleukin-2 (IL-2) and IL-3 signaling by accelerating SOCS3 degradation. Mol Cell Biol 25(20):9115–9126

    CAS  PubMed Central  PubMed  Google Scholar 

  286. Karve TM et al (2012) BRCA1 regulates follistatin function in ovarian cancer and human ovarian surface epithelial cells. PLoS ONE 7(6):e37697

    CAS  PubMed Central  PubMed  Google Scholar 

  287. Wordinger RJ et al (2002) Expression of bone morphogenetic proteins (BMP), BMP receptors, and BMP associated proteins in human trabecular meshwork and optic nerve head cells and tissues. Mol Vis 8:241–250

    CAS  PubMed  Google Scholar 

  288. Abe Y et al (2004) Follistatin restricts bone morphogenetic protein (BMP)-2 action on the differentiation of osteoblasts in fetal rat mandibular cells. J Bone Miner Res Off J Am Soc Bone Miner Res 19(8):1302–1307

    CAS  Google Scholar 

  289. Fainsod A et al (1997) The dorsalizing and neural inducing gene follistatin is an antagonist of BMP-4. Mech Dev 63(1):39–50

    CAS  PubMed  Google Scholar 

  290. Shimonaka M et al (1991) Follistatin binds to both activin and inhibin through the common subunit. Endocrinology 128(6):3313–3315

    CAS  PubMed  Google Scholar 

  291. Yao HH et al (2004) Follistatin operates downstream of Wnt4 in mammalian ovary organogenesis. Dev Dyn Off Pub Am Assoc Anat 230(2):210–215

    CAS  Google Scholar 

  292. Ogino H et al (2008) Follistatin suppresses the production of experimental multiple-organ metastasis by small cell lung cancer cells in natural killer cell-depleted SCID mice. Clin Cancer Res Off J Am Assoc Cancer Res 14(3):660–667

    CAS  Google Scholar 

  293. Boedtkjer E et al (2013) Contribution of Na+, HCO3(-)-cotransport to cellular pH control in human breast cancer: a role for the breast cancer susceptibility locus NBCn1 (SLC4A7). Int J Cancer J Int Cancer 132(6):1288–1299

    CAS  Google Scholar 

  294. Italiano D et al (2012) Identification of NCF2/p67phox as a novel p53 target gene. Cell Cycle 11(24):4589–4596

    CAS  PubMed Central  PubMed  Google Scholar 

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  1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Pour Sina Street, P.O. Box: 14176-13151, Keshavarz Boulevard, Tehran, Iran

    Hassan Fazilaty & Parvin Mehdipour

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  1. Hassan Fazilaty
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  2. Parvin Mehdipour
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Correspondence to Parvin Mehdipour.

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Fazilaty, H., Mehdipour, P. Genetics of breast cancer bone metastasis: a sequential multistep pattern. Clin Exp Metastasis 31, 595–612 (2014). https://doi.org/10.1007/s10585-014-9642-9

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