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The RUNX family in breast cancer: relationships with estrogen signaling

Oncogene volume 32, pages 2121–2130 (2013)Cite this article

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Abstract

The three RUNX family members are lineage specific master regulators, which also have important, context-dependent roles in carcinogenesis as either tumor suppressors or oncogenes. Here we review evidence for such roles in breast cancer (BCa). RUNX1, the predominant RUNX family member in breast epithelial cells, has a tumor suppressor role reflected by many somatic mutations found in primary tumor biopsies. The classical tumor suppressor gene RUNX3 does not consist of such a mutation hot spot, but it too seems to inhibit BCa; it is often inactivated in human BCa tumors and its haploinsufficiency in mice leads to spontaneous BCa development. The tumor suppressor activities of RUNX1 and RUNX3 are mediated in part by antagonism of estrogen signaling, a feature recently attributed to RUNX2 as well. Paradoxically, however RUNX2, a master osteoblast regulator, has been implicated in various aspects of metastasis in general and bone metastasis in particular. Reciprocating the anti-estrogenic tumor suppressor activity of RUNX proteins, inhibition of RUNX2 by estrogens may help explain their context-dependent anti-metastatic roles. Such roles are reserved to non-osseous metastasis, because ERα is associated with increased, not decreased skeletal dissemination of BCa cells. Finally, based on diverse expression patterns in BCa subtypes, the successful use of future RUNX-based therapies will most likely require careful patient selection.

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References

  1. Blyth K, Cameron ER, Neil JC . The RUNX genes: gain or loss of function in cancer. Nat Rev Cancer 2005; 5: 376–387.

    CAS  PubMed  Google Scholar 

  2. Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR . AML1 the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 1996; 84: 321–330.

    CAS  PubMed  Google Scholar 

  3. Komori T . Regulation of bone development and extracellular matrix protein genes by RUNX2. Cell Tissue Res 2010; 339: 189–195.

    CAS  PubMed  Google Scholar 

  4. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997; 89: 755–764.

    CAS  PubMed  Google Scholar 

  5. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 1997; 89: 765–771.

    CAS  PubMed  Google Scholar 

  6. Fukamachi H, Ito K . Growth regulation of gastric epithelial cells by Runx3. Oncogene 2004; 23: 4330–4335.

    CAS  PubMed  Google Scholar 

  7. Levanon D, Bettoun D, Harris-Cerruti C, Woolf E, Negreanu V, Eilam R et al. The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons. EMBO J 2002; 21: 3454–3463.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ et al. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 2002; 109: 113–124.

    CAS  PubMed  Google Scholar 

  9. Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 1999; 23: 166–175.

    CAS  PubMed  Google Scholar 

  10. Mundlos S . Cleidocranial dysplasia: clinical and molecular genetics. J Med Genet 1999; 36: 177–182.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Pratap J, Lian JB, Stein GS . Metastatic bone disease: role of transcription factors and future targets. Bone 2011; 48: 30–36.

    CAS  PubMed  Google Scholar 

  12. Bagchi A, Mills AA . The quest for the 1p36 tumor suppressor. Cancer Res 2008; 68: 2551–2556.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang L, Brugge JS, Janes KA . Intersection of FOXO- and RUNX1-mediated gene expression programs in single breast epithelial cells during morphogenesis and tumor progression. Proc Natl Acad Sci USA 2011; 108: E803–E812.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Huang B, Qu Z, Ong CW, Tsang YH, Xiao G, Shapiro D et al. RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor alpha. Oncogene 2012; 31: 527–534.

    CAS  PubMed  Google Scholar 

  15. Chimge NO, Baniwal SK, Luo J, Coetzee S, Khalid O, Berman BP et al. Opposing effects of Runx2 and estradiol on breast cancer cell proliferation: in vitro identification of reciprocally regulated gene signature related to clinical letrozole responsiveness. Clin Cancer Res 2012; 18: 901–911.

    CAS  PubMed  Google Scholar 

  16. Javed A, Barnes GL, Pratap J, Antkowiak T, Gerstenfeld LC, van Wijnen AJ et al. Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo. Proc Natl Acad Sci USA 2005; 102: 1454–1459.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Pratap J, Imbalzano KM, Underwood JM, Cohet N, Gokul K, Akech J et al. Ectopic runx2 expression in mammary epithelial cells disrupts formation of normal acini structure: implications for breast cancer progression. Cancer Res 2009; 69: 6807–6814.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Pratap J, Wixted JJ, Gaur T, Zaidi SK, Dobson J, Gokul KD et al. Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells. Cancer Res 2008; 68: 7795–7802.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Baniwal SK, Khalid O, Gabet Y, Shah RR, Purcell DJ, Mav D et al. Runx2 transcriptome of prostate cancer cells: insights into invasiveness and bone metastasis. Mol Cancer 2010; 9: 258.

    PubMed  PubMed Central  Google Scholar 

  20. Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA et al. Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene 2010; 29: 811–821.

    CAS  PubMed  Google Scholar 

  21. Chuang LS, Ito Y . RUNX3 is multifunctional in carcinogenesis of multiple solid tumors. Oncogene 2010; 29: 2605–2615.

    CAS  PubMed  Google Scholar 

  22. Mangan JK, Speck NA . RUNX1 mutations in clonal myeloid disorders: from conventional cytogenetics to next generation sequencing. A story 40 years in the making. Crit Rev Oncog 2011; 16: 77–91.

    PubMed  PubMed Central  Google Scholar 

  23. De Braekeleer E, Ferec C, De Braekeleer M . RUNX1 translocations in malignant hemopathies. Anticancer Res 2009; 29: 1031–1037.

    CAS  PubMed  Google Scholar 

  24. Chen LF . Tumor suppressor function of RUNX3 in breast cancer. J Cell Biochem 2012; 113: 1470–1477.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Blyth K, Vaillant F, Jenkins A, McDonald L, Pringle MA, Huser C et al. Runx2 in normal tissues and cancer cells: a developing story. Blood Cells Mol Dis 2010; 45: 117–123.

    CAS  PubMed  Google Scholar 

  26. Janes KA . RUNX1 and its understudied role in breast cancer. Cell Cycle 2011; 10: 3461–3465.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C et al. Alternative isoform regulation in human tissue transcriptomes. Nature 2008; 456: 470–476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW et al. Whole genome analysis informs breast cancer response to aromatase inhibition. Nature 2012; 486: 353–360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Network TCGA. Comprehensive molecular portraits of human breast tumors. Nature (in press).

  30. Ramaswamy S, Ross KN, Lander ES, Golub TR . A molecular signature of metastasis in primary solid tumors. Nat Genet 2003; 33: 49–54.

    Article  CAS  PubMed  Google Scholar 

  31. Kadota M, Yang HH, Gomez B, Sato M, Clifford RJ, Meerzaman D et al. Delineating genetic alterations for tumor progression in the MCF10A series of breast cancer cell lines. PLoS One 2010; 5: e9201.

    PubMed  PubMed Central  Google Scholar 

  32. Liu YN, Lee WW, Wang CY, Chao TH, Chen Y, Chen JH . Regulatory mechanisms controlling human E-cadherin gene expression. Oncogene 2005; 24: 8277–8290.

    CAS  PubMed  Google Scholar 

  33. Stender JD, Kim K, Charn TH, Komm B, Chang KC, Kraus WL et al. Genome-wide analysis of estrogen receptor alpha DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation. Mol Cell Biol 2010; 30: 3943–3955.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Lau QC, Raja E, Salto-Tellez M, Liu Q, Ito K, Inoue M et al. RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer. Cancer Res 2006; 66: 6512–6520.

    CAS  PubMed  Google Scholar 

  35. Jiang Y, Tong D, Lou G, Zhang Y, Geng J . Expression of RUNX3 gene, methylation status and clinicopathological significance in breast cancer and breast cancer cell lines. Pathobiology 2008; 75: 244–251.

    CAS  PubMed  Google Scholar 

  36. Subramaniam MM, Chan JY, Soong R, Ito K, Ito Y, Yeoh KG et al. RUNX3 inactivation by frequent promoter hypermethylation and protein mislocalization constitute an early event in breast cancer progression. Breast Cancer Res Treat 2009; 113: 113–121.

    CAS  PubMed  Google Scholar 

  37. Kim TY, Lee HJ, Hwang KS, Lee M, Kim JW, Bang YJ et al. Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma. Lab Invest 2004; 84: 479–484.

    CAS  PubMed  Google Scholar 

  38. Suzuki M, Shigematsu H, Shames DS, Sunaga N, Takahashi T, Shivapurkar N et al. DNA methylation-associated inactivation of TGFbeta-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers. Br J Cancer 2005; 93: 1029–1037.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Hwang KT, Han W, Bae JY, Hwang SE, Shin HJ, Lee JE et al. Downregulation of the RUNX3 gene by promoter hypermethylation and hemizygous deletion in breast cancer. JKorean Med Sci 2007; 22 (Suppl): S24–S31.

    CAS  Google Scholar 

  40. Tan SH, Ida H, Lau QC, Goh BC, Chieng WS, Loh M et al. Detection of promoter hypermethylation in serum samples of cancer patients by methylation-specific polymerase chain reaction for tumour suppressor genes including RUNX3. Oncol Rep 2007; 18: 1225–1230.

    CAS  PubMed  Google Scholar 

  41. Park SY, Kwon HJ, Choi Y, Lee HE, Kim SW, Kim JH et al. Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes. Mod Pathol 2012; 25: 185–196.

    CAS  PubMed  Google Scholar 

  42. Park SY, Kwon HJ, Lee HE, Ryu HS, Kim SW, Kim JH et al. Promoter CpG island hypermethylation during breast cancer progression. Virchows Arch 2011; 458: 73–84.

    CAS  PubMed  Google Scholar 

  43. Cheng AS, Culhane AC, Chan MW, Venkataramu CR, Ehrich M, Nasir A et al. Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome. Cancer Res 2008; 68: 1786–1796.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kouros-Mehr H, Werb Z . Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn 2006; 235: 3404–3412.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Shore P . A role for Runx2 in normal mammary gland and breast cancer bone metastasis. J Cell Biochem 2005; 96: 484–489.

    CAS  PubMed  Google Scholar 

  46. Inman CK, Shore P . The osteoblast transcription factor Runx2 is expressed in mammary epithelial cells and mediates osteopontin expression. J Biol Chem 2003; 278: 48684–48689.

    CAS  PubMed  Google Scholar 

  47. Pratap J, Galindo M, Zaidi SK, Vradii D, Bhat BM, Robinson JA et al. Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts. Cancer Res 2003; 63: 5357–5362.

    CAS  PubMed  Google Scholar 

  48. Galindo M, Pratap J, Young DW, Hovhannisyan H, Im HJ, Choi JY et al. The bone-specific expression of Runx2 oscillates during the cell cycle to support a G1-related antiproliferative function in osteoblasts. J Biol Chem 2005; 280: 20274–20285.

    CAS  PubMed  Google Scholar 

  49. Young DW, Hassan MQ, Pratap J, Galindo M, Zaidi SK, Lee SH et al. Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2. Nature 2007; 445: 442–446.

    CAS  PubMed  Google Scholar 

  50. Baniwal SK, Khalid O, Sir D, Buchanan G, Coetzee GA, Frenkel B . Repression of Runx2 by androgen receptor (AR) in osteoblasts and prostate cancer cells: AR binds Runx2 and abrogates its recruitment to DNA. Mol Endocrinol 2009; 23: 1203–1214.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Khalid O, Baniwal SK, Purcell DJ, Leclerc N, Gabet Y, Stallcup MR et al. Modulation of Runx2 activity by estrogen receptor-alpha: implications for osteoporosis and breast cancer. Endocrinology 2008; 149: 5984–5995.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Little GH, Noushmehr H, Baniwal SK, Berman BP, Coetzee GA, Frenkel B . Genome-wide Runx2 occupancy in prostate cancer cells suggests a role in regulating secretion. Nucleic Acids Res 2012; 40: 3538–3547.

    CAS  PubMed  Google Scholar 

  53. Cicatiello L, Mutarelli M, Grober OM, Paris O, Ferraro L, Ravo M et al. Estrogen receptor alpha controls a gene network in luminal-like breast cancer cells comprising multiple transcription factors and microRNAs. Am J Pathol 2010; 176: 2113–2130.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Stewart M, MacKay N, Cameron ER, Neil JC . The common retroviral insertion locus Dsi1 maps 30 kilobases upstream of the P1 promoter of the murine Runx3/Cbfa3/Aml2 gene. J Virol 2002; 76: 4364–4369.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Miething C, Grundler R, Mugler C, Brero S, Hoepfl J, Geigl J et al. Retroviral insertional mutagenesis identifies RUNX genes involved in chronic myeloid leukemia disease persistence under imatinib treatment. Proc Natl Acad Sci USA 2007; 104: 4594–4599.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Dupuy AJ, Akagi K, Largaespada DA, Copeland NG, Jenkins NA . Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 2005; 436: 221–226.

    CAS  PubMed  Google Scholar 

  57. Rahrmann EP, Collier LS, Knutson TP, Doyal ME, Kuslak SL, Green LE et al. Identification of PDE4D as a proliferation promoting factor in prostate cancer using a sleeping beauty transposon-based somatic mutagenesis screen. Cancer Res 2009; 69: 4388–4397.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Li J, Shen H, Himmel KL, Dupuy AJ, Largaespada DA, Nakamura T et al. Leukaemia disease genes: large-scale cloning and pathway predictions. Nat Genet 1999; 23: 348–353.

    CAS  PubMed  Google Scholar 

  59. Mikkers H, Allen J, Knipscheer P, Romeijn L, Hart A, Vink E et al. High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nat Genet 2002; 32: 153–159.

    CAS  PubMed  Google Scholar 

  60. Suzuki T, Shen H, Akagi K, Morse HC, Malley JD, Naiman DQ et al. New genes involved in cancer identified by retroviral tagging. Nat Genet 2002; 32: 166–174.

    CAS  PubMed  Google Scholar 

  61. Stewart M, Terry A, Hu M, O′Hara M, Blyth K, Baxter E et al. Proviral insertions induce the expression of bone-specific isoforms of PEBP2alphaA (CBFA1): evidence for a new myc collaborating oncogene. Proc Natl Acad Sci USA 1997; 94: 8646–8651.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Vaillant F, Blyth K, Terry A, Bell M, Cameron ER, Neil J et al. A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with myc. Oncogene 1999; 18: 7124–7134.

    CAS  PubMed  Google Scholar 

  63. Blyth K, Slater N, Hanlon L, Bell M, Mackay N, Stewart M et al. Runx1 promotes B-cell survival and lymphoma development. Blood Cells Mol Dis 2009; 43: 12–19.

    CAS  PubMed  Google Scholar 

  64. Hoi CS, Lee SE, Lu SY, McDermitt DJ, Osorio KM, Piskun CM et al. Runx1 directly promotes proliferation of hair follicle stem cells and epithelial tumor formation in mouse skin. Mol Cell Biol 2010; 30: 2518–2536.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Niini T, Kanerva J, Vettenranta K, Saarinen-Pihkala UM, Knuutila S . AML1 gene amplification: a novel finding in childhood acute lymphoblastic leukemia. Haematologica 2000; 85: 362–366.

    CAS  PubMed  Google Scholar 

  66. Harewood L, Robinson H, Harris R, Al-Obaidi MJ, Jalali GR, Martineau M et al. Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases. Leukemia 2003; 17: 547–553.

    CAS  PubMed  Google Scholar 

  67. Robinson HM, Broadfield ZJ, Cheung KL, Harewood L, Harris RL, Jalali GR et al. Amplification of AML1 in acute lymphoblastic leukemia is associated with a poor outcome. Leukemia 2003; 17: 2249–2250.

    CAS  PubMed  Google Scholar 

  68. Cameron ER, Blyth K, Hanlon L, Kilbey A, Mackay N, Stewart M et al. The Runx genes as dominant oncogenes. Blood Cells Mol Dis 2003; 30: 194–200.

    CAS  PubMed  Google Scholar 

  69. Planaguma J, Diaz-Fuertes M, Gil-Moreno A, Abal M, Monge M, Garcia A et al. A differential gene expression profile reveals overexpression of RUNX1/AML1 in invasive endometrioid carcinoma. Cancer Res 2004; 64: 8846–8853.

    CAS  PubMed  Google Scholar 

  70. Doll A, Gonzalez M, Abal M, Llaurado M, Rigau M, Colas E et al. An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis. Int J Cancer 2009; 125: 257–263.

    CAS  PubMed  Google Scholar 

  71. Planaguma J, Liljestrom M, Alameda F, Butzow R, Virtanen I, Reventos J et al. Matrix metalloproteinase-2 and matrix metalloproteinase-9 codistribute with transcription factors RUNX1/AML1 and ETV5/ERM at the invasive front of endometrial and ovarian carcinoma. Hum Pathol 2011; 42: 57–67.

    CAS  PubMed  Google Scholar 

  72. Tsunematsu T, Kudo Y, Iizuka S, Ogawa I, Fujita T, Kurihara H et al. RUNX3 has an oncogenic role in head and neck cancer. PLoS One 2009; 4: e5892.

    PubMed  PubMed Central  Google Scholar 

  73. Salto-Tellez M, Peh BK, Ito K, Tan SH, Chong PY, Han HC et al. RUNX3 protein is overexpressed in human basal cell carcinomas. Oncogene 2006; 25: 7646–7649.

    CAS  PubMed  Google Scholar 

  74. Nevadunsky NS, Barbieri JS, Kwong J, Merritt MA, Welch WR, Berkowitz RS et al. RUNX3 protein is overexpressed in human epithelial ovarian cancer. Gynecol Oncol 2009; 112: 325–330.

    CAS  PubMed  Google Scholar 

  75. Blyth K, Vaillant F, Hanlon L, Mackay N, Bell M, Jenkins A et al. Runx2 and MYC collaborate in lymphoma development by suppressing apoptotic and growth arrest pathways in vivo. Cancer Res 2006; 66: 2195–2201.

    CAS  PubMed  Google Scholar 

  76. Kuo YH, Zaidi SK, Gornostaeva S, Komori T, Stein GS, Castilla LH . Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice. Blood 2009; 113: 3323–3332.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Lau CC, Harris CP, Lu XY, Perlaky L, Gogineni S, Chintagumpala M et al. Frequent amplification and rearrangement of chromosomal bands 6p12-p21 and 17p11.2 in osteosarcoma. Genes Chromosomes Cancer 2004; 39: 11–21.

    PubMed  Google Scholar 

  78. Forus A, Weghuis DO, Smeets D, Fodstad O, Myklebost O, Geurts van Kessel A . Comparative genomic hybridization analysis of human sarcomas: II. Identification of novel amplicons at 6p and 17p in osteosarcomas. Genes Chromosomes Cancer 1995; 14: 15–21.

    CAS  PubMed  Google Scholar 

  79. Sase T, Suzuki T, Miura K, Shiiba K, Sato I, Nakamura Y et al. Runt-related transcription factor 2 (RUNX2) in human colon carcinoma: a potent prognostic factor associated with estrogen receptor. Int J Cancer (e-pub ahead of print 7 March 2012; doi:10.1002/ijc.27525).

    CAS  PubMed  Google Scholar 

  80. Kayed H, Jiang X, Keleg S, Jesnowski R, Giese T, Berger MR et al. Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer. Br J Cancer 2007; 97: 1106–1115.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Endo T, Ohta K, Kobayashi T . Expression and function of Cbfa-1/Runx2 in thyroid papillary carcinoma cells. J Clin Endocrinol Metab 2008; 93: 2409–2412.

    CAS  PubMed  Google Scholar 

  82. Lim M, Zhong C, Yang S, Bell AM, Cohen MB, Roy-Burman P . Runx2 regulates survivin expression in prostate cancer cells. Lab Invest 2010; 90: 222–233.

    CAS  PubMed  Google Scholar 

  83. Hsu YL, Huang MS, Yang CJ, Hung JY, Wu LY, Kuo PL . Lung tumor-associated osteoblast-derived bone morphogenetic protein-2 increased epithelial-to-mesenchymal transition of cancer by Runx2/Snail signaling pathway. J Biol Chem 2011; 286: 37335–37346.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Vasko V, Espinosa AV, Scouten W, He H, Auer H, Liyanarachchi S et al. Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc Natl Acad Sci US A 2007; 104: 2803–2808.

    CAS  Google Scholar 

  85. Leong DT, Lim J, Goh X, Pratap J, Pereira BP, Kwok HS et al. Cancer-related ectopic expression of the bone-related transcription factor RUNX2 in non-osseous metastatic tumor cells is linked to cell proliferation and motility. Breast Cancer Res 2010; 12: R89.

    PubMed  PubMed Central  Google Scholar 

  86. Chimge NO, Baniwal SK, Little GH, Chen YB, Kahn M, Tripathy D et al. Regulation of breast cancer metastasis by Runx2 and estrogen signaling: role of SNAI2. Breast Cancer Res 2011; 13: R127.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Onodera Y, Miki Y, Suzuki T, Takagi K, Akahira J, Sakyu T et al. Runx2 in human breast carcinoma: its potential roles in cancer progression. Cancer Sci 2010; 101: 2670–2675.

    CAS  PubMed  Google Scholar 

  88. Koeneman KS, Yeung F, Chung LW . Osteomimetic properties of prostate cancer cells: a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate 1999; 39: 246–261.

    CAS  PubMed  Google Scholar 

  89. Coleman RE . Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006; 12: 6243–6249.

    Google Scholar 

  90. Carlinfante G, Vassiliou D, Svensson O, Wendel M, Heinegard D, Andersson G . Differential expression of osteopontin and bone sialoprotein in bone metastasis of breast and prostate carcinoma. Clin Exp Metastasis 2003; 20: 437–444.

    CAS  PubMed  Google Scholar 

  91. Thalmann GN, Sikes RA, Devoll RE, Kiefer JA, Markwalder R, Klima I et al. Osteopontin: possible role in prostate cancer progression. Clin Cancer Res 1999; 5: 2271–2277.

    CAS  PubMed  Google Scholar 

  92. Chen G, Sircar K, Aprikian A, Potti A, Goltzman D, Rabbani SA . Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation. Cancer 2006; 107: 289–298.

    CAS  PubMed  Google Scholar 

  93. Patani N, Jouhra F, Jiang W, Mokbel K . Osteopontin expression profiles predict pathological and clinical outcome in breast cancer. Anticancer Res 2008; 28: 4105–4110.

    CAS  PubMed  Google Scholar 

  94. Cross SS, Harrison RF, Balasubramanian SP, Lippitt JM, Evans CA, Reed MW et al. Expression of receptor activator of nuclear factor kappabeta ligand (RANKL) and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) in breast cancer, and their relations with osteoprotegerin, oestrogen receptor, and clinicopathological variables. J Clin Pathol 2006; 59: 716–720.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Bellahcene A, Merville MP, Castronovo V . Expression of bone sialoprotein, a bone matrix protein, in human breast cancer. Cancer Res 1994; 54: 2823–2826.

    CAS  PubMed  Google Scholar 

  96. Tsoli E, Tsantoulis PK, Papalambros A, Perunovic B, England D, Rawlands DA et al. Simultaneous evaluation of maspin and CXCR4 in patients with breast cancer. J Clin Pathol 2007; 60: 261–266.

    CAS  PubMed  Google Scholar 

  97. Brubaker KD, Vessella RL, Brown LG, Corey E . Prostate cancer expression of runt-domain transcription factor Runx2, a key regulator of osteoblast differentiation and function. Prostate 2003; 56: 13–22.

    CAS  PubMed  Google Scholar 

  98. Das K, Leong DT, Gupta A, Shen L, Putti T, Stein GS et al. Positive association between nuclear Runx2 and oestrogen-progesterone receptor gene expression characterises a biological subtype of breast cancer. Eur J Cancer 2009; 45: 2239–2248.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Altieri DC . Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 2008; 8: 61–70.

    CAS  PubMed  Google Scholar 

  100. Morrissey C, Brown LG, Pitts TE, Vessella RL, Corey E . Bone morphogenetic protein 7 is expressed in prostate cancer metastases and its effects on prostate tumor cells depend on cell phenotype and the tumor microenvironment. Neoplasia 2010; 12: 192–205.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Yang S, Lim M, Pham LK, Kendall SE, Reddi AH, Altieri DC et al. Bone morphogenetic protein 7 protects prostate cancer cells from stress-induced apoptosis via both Smad and c-Jun NH2-terminal kinase pathways. Cancer Res 2006; 66: 4285–4290.

    CAS  PubMed  Google Scholar 

  102. Alarmo EL, Parssinen J, Ketolainen JM, Savinainen K, Karhu R, Kallioniemi A . BMP7 influences proliferation, migration, and invasion of breast cancer cells. Cancer Lett 2009; 275: 35–43.

    CAS  PubMed  Google Scholar 

  103. Barnes GL, Hebert KE, Kamal M, Javed A, Einhorn TA, Lian JB et al. Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastases-associated osteolytic disease. Cancer Res 2004; 64: 4506–4513.

    CAS  PubMed  Google Scholar 

  104. Pratap J, Javed A, Languino LR, van Wijnen AJ, Stein JL, Stein GS et al. The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion. Mol Cell Biol 2005; 25: 8581–8591.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Barnes GL, Javed A, Waller SM, Kamal MH, Hebert KE, Hassan MQ et al. Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells. Cancer Res 2003; 63: 2631–2637.

    CAS  PubMed  Google Scholar 

  106. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G . Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997; 89: 747–754.

    CAS  PubMed  Google Scholar 

  107. Mendoza-Villanueva D, Zeef L, Shore P . Metastatic breast cancer cells inhibit osteoblast differentiation through the Runx2/CBFbeta-dependent expression of the Wnt antagonist, sclerostin. Breast Cancer Res 2011; 13: R106.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Weilbaecher KN, Guise TA, McCauley LK . Cancer to bone: a fatal attraction. Nat Rev Cancer 2011; 11: 411–425.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Roodman GD . Mechanisms of bone metastasis. N Eng J Med 2004; 350: 1655–1664.

    CAS  Google Scholar 

  110. Baniwal SK, Shah PK, Shi Y, Haduong JH, Declerck YA, Gabet Y et al. Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells. Osteoporos Int 2012; 23: 1399–1413.

    CAS  PubMed  Google Scholar 

  111. Liu W, Toyosawa S, Furuichi T, Kanatani N, Yoshida C, Liu Y et al. Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures. J Cell Biol 2001; 155: 157–166.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Geoffroy V, Kneissel M, Fournier B, Boyde A, Matthias P . High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage. Mol Cell Biol 2002; 22: 6222–6233.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Frenkel B, Hong A, Baniwal SK, Coetzee GA, Ohlsson C, Khalid O et al. Regulation of adult bone turnover by sex steroids. J Cell Physiol 2010; 224: 305–310.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Maruyama Z, Yoshida CA, Furuichi T, Amizuka N, Ito M, Fukuyama R et al. Runx2 determines bone maturity and turnover rate in postnatal bone development and is involved in bone loss in estrogen deficiency. Dev Dyn 2007; 236: 1876–1890.

    CAS  PubMed  Google Scholar 

  115. He N, Xiao Z, Yin T, Stubbs J, Li L, Quarles LD . Inducible expression of Runx2 results in multiorgan abnormalities in mice. J Cell Biochem 2011; 112: 653–665.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Platet N, Cunat S, Chalbos D, Rochefort H, Garcia M . Unliganded and liganded estrogen receptors protect against cancer invasion via different mechanisms. Mol Endocrinol 2000; 14: 999–1009.

    CAS  PubMed  Google Scholar 

  117. Ellis MJ, Gao F, Dehdashti F, Jeffe DB, Marcom PK, Carey LA et al. Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. Jama 2009; 302: 774–780.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Maynadier M, Ramirez JM, Cathiard AM, Platet N, Gras D, Gleizes M et al. Unliganded estrogen receptor alpha inhibits breast cancer cell growth through interaction with a cyclin-dependent kinase inhibitor (p21(WAF1)). Faseb J 2008; 22: 671–681.

    CAS  PubMed  Google Scholar 

  119. Ye Y, Xiao Y, Wang W, Yearsley K, Gao JX, Shetuni B et al. ERalpha signaling through slug regulates E-cadherin and EMT. Oncogene 2010; 29: 1451–1462.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 2003; 3: 537–549.

    CAS  PubMed  Google Scholar 

  122. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD et al. Genes that mediate breast cancer metastasis to lung. Nature 2005; 436: 518–524.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Hess KR, Pusztai L, Buzdar AU, Hortobagyi GN . Estrogen receptors and distinct patterns of breast cancer relapse. Breast Cancer Res Treat 2003; 78: 105–118.

    CAS  PubMed  Google Scholar 

  124. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA et al. Molecular portraits of human breast tumours. Nature 2000; 406: 747–752.

    CAS  PubMed  Google Scholar 

  125. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 2003; 100: 8418–8423.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 2009; 27: 1160–1167.

    PubMed  PubMed Central  Google Scholar 

  127. Spender LC, Whiteman HJ, Karstegl CE, Farrell PJ . Transcriptional cross-regulation of RUNX1 by RUNX3 in human B cells. Oncogene 2005; 24: 1873–1881.

    CAS  PubMed  Google Scholar 

  128. Brady G, Whiteman HJ, Spender LC, Farrell PJ . Downregulation of RUNX1 by RUNX3 requires the RUNX3 VWRPY sequence and is essential for Epstein-Barr virus-driven B-cell proliferation. J Virol 2009; 83: 6909–6916.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Smith N, Dong Y, Lian JB, Pratap J, Kingsley PD, van Wijnen AJ et al. Overlapping expression of Runx1(Cbfa2) and Runx2(Cbfa1) transcription factors supports cooperative induction of skeletal development. J Cell Physiol 2005; 203: 133–143.

    CAS  PubMed  Google Scholar 

  130. Pencovich N, Jaschek R, Tanay A, Groner Y . Dynamic combinatorial interactions of RUNX1 and cooperating partners regulates megakaryocytic differentiation in cell line models. Blood 2011; 117: e1–14.

    CAS  PubMed  Google Scholar 

  131. Bae SC, Ito Y . Regulation mechanisms for the heterodimeric transcription factor, PEBP2/CBF. Histol Histopatho 1999; 14: 1213–1221.

    CAS  Google Scholar 

  132. Wotton S, Terry A, Kilbey A, Jenkins A, Herzyk P, Cameron E et al. Gene array analysis reveals a common Runx transcriptional programme controlling cell adhesion and survival. Oncogene 2008; 27: 5856–5866.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. van der Deen M, Akech J, Lapointe D, Gupta S, Young DW, Montecino MA et al. Genomic promoter occupancy of runt-related transcription factor RUNX2 in osteosarcoma cells identifies genes involved in cell adhesion and motility. J Biol Chem 2012; 287: 4503–4517.

    CAS  PubMed  Google Scholar 

  134. Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V et al. A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev 1999; 13: 1025–1036.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Li D, Sinha KK, Hay MA, Rinaldi CR, Saunthararajah Y, Nucifora G . RUNX1-RUNX1 homodimerization modulates RUNX1 activity and function. J Biol Chem 2007; 282: 13542–13551.

    CAS  PubMed  Google Scholar 

  136. Mendoza-Villanueva D, Deng W, Lopez-Camacho C, Shore P . The Runx transcriptional co-activator, CBFbeta, is essential for invasion of breast cancer cells. Mol Cancer 2010; 9: 171.

    PubMed  PubMed Central  Google Scholar 

  137. Rowley JD . Identificaton of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet 1973; 16: 109–112.

    CAS  PubMed  Google Scholar 

  138. Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y, Ohki M . t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc Natl Acad Sci USA 1991; 88: 10431–10434.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Lam K, Zhang DE . RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. Front Biosci 2012; 17: 1120–1139.

    CAS  PubMed Central  Google Scholar 

  140. De Braekeleer E, Douet-Guilbert N, Le Bris MJ, Morel F, Ferec C, De Braekeleer M . RUNX1-MTG16 fusion gene in acute myeloblastic leukemia with t(16;21)(q24;q22): case report and review of the literature. Cancer Genet Cytogenet 2008; 185: 47–50.

    CAS  PubMed  Google Scholar 

  141. Gaidzik VI, Bullinger L, Schlenk RF, Zimmermann AS, Rock J, Paschka P et al. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J Clin Oncol 2011; 29: 1364–1372.

    PubMed  Google Scholar 

  142. Radtke I, Mullighan CG, Ishii M, Su X, Cheng J, Ma J et al. Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. Proc Natl Acad Sci USA 2009; 106: 12944–12949.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Nucifora G, Begy CR, Kobayashi H, Roulston D, Claxton D, Pedersen-Bjergaard J et al. Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations. Proc Natl Acad Sci USA 1994; 91: 4004–4008.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H et al. Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia. EMBO J 1994; 13: 504–510.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Nucifora G, Rowley JD . AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Blood 1995; 86: 1–14.

    CAS  PubMed  Google Scholar 

  146. Nucifora G, Begy CR, Erickson P, Drabkin HA, Rowley JD . The 3;21 translocation in myelodysplasia results in a fusion transcript between the AML1 gene and the gene for EAP, a highly conserved protein associated with the Epstein-Barr virus small RNA EBER 1. Proc Natl Acad Sci USA 1993; 90: 7784–7788.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Nucifora G, Birn DJ, Espinosa R, Erickson P, LeBeau MM, Roulston D et al. Involvement of the AML1 gene in the t(3;21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis. Blood 1993; 81: 2728–2734.

    CAS  PubMed  Google Scholar 

  148. Hromas R, Shopnick R, Jumean HG, Bowers C, Varella-Garcia M, Richkind K . A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations. Blood 2000; 95: 4011–4013.

    CAS  PubMed  Google Scholar 

  149. Roulston D, Espinosa R, Nucifora G, Larson RA, Le Beau MM, Rowley JD . CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. Blood 1998; 92: 2879–2885.

    CAS  PubMed  Google Scholar 

  150. Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Takeuchi K, Maki K et al. Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis. Blood 2000; 96: 3154–3160.

    CAS  PubMed  Google Scholar 

  151. Harada H, Harada Y, Tanaka H, Kimura A, Inaba T . Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. Blood 2003; 101: 673–680.

    CAS  PubMed  Google Scholar 

  152. Harada H, Harada Y, Niimi H, Kyo T, Kimura A, Inaba T . High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood 2004; 103: 2316–2324.

    CAS  PubMed  Google Scholar 

  153. Steensma DP, Gibbons RJ, Mesa RA, Tefferi A, Higgs DR . Somatic point mutations in RUNX1/CBFA2/AML1 are common in high-risk myelodysplastic syndrome, but not in myelofibrosis with myeloid metaplasia. Eur J Haematol 2005; 74: 47–53.

    CAS  PubMed  Google Scholar 

  154. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G et al. Clinical effect of point mutations in myelodysplastic syndromes. N Eng J Med 2011; 364: 2496–2506.

    CAS  Google Scholar 

  155. Dicker F, Haferlach C, Sundermann J, Wendland N, Weiss T, Kern W et al. Mutation analysis for RUNX1, MLL-PTD, FLT3-ITD, NPM1 and NRAS in 269 patients with MDS or secondary AML. Leukemia 2010; 24: 1528–1532.

    CAS  PubMed  Google Scholar 

  156. Kohlmann A, Grossmann V, Klein HU, Schindela S, Weiss T, Kazak B et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol 2010; 28: 3858–3865.

    CAS  PubMed  Google Scholar 

  157. Romana SP, Poirel H, Leconiat M, Flexor MA, Mauchauffe M, Jonveaux P et al. High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. Blood 1995; 86: 4263–4269.

    CAS  PubMed  Google Scholar 

  158. Douet-Guilbert N, Morel F, Le Bris MJ, Herry A, Le Calvez G, Marion V et al. A fluorescence in situ hybridization study of TEL-AML1 fusion gene in B-cell acute lymphoblastic leukemia (1984-2001). Cancer Genet Cytogenet 2003; 144: 143–147.

    CAS  PubMed  Google Scholar 

  159. Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Bray-Ward P et al. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci USA 1995; 92: 4917–4921.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Hiebert SW, Sun W, Davis JN, Golub T, Shurtleff S, Buijs A et al. The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription. Mol Cell Biol 1996; 16: 1349–1355.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood 2002; 99: 1364–1372.

    CAS  PubMed  Google Scholar 

  162. Tang JL, Hou HA, Chen CY, Liu CY, Chou WC, Tseng MH et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 2009; 114: 5352–5361.

    CAS  PubMed  Google Scholar 

  163. Silva FP, Morolli B, Storlazzi CT, Anelli L, Wessels H, Bezrookove V et al. Identification of RUNX1/AML1 as a classical tumor suppressor gene. Oncogene 2003; 22: 538–547.

    CAS  PubMed  Google Scholar 

  164. Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias. Blood 1999; 93: 1817–1824.

    CAS  PubMed  Google Scholar 

  165. Gelsi-Boyer V, Trouplin V, Adelaide J, Aceto N, Remy V, Pinson S et al. Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes. BMC Cancer 2008; 8: 299.

    PubMed  PubMed Central  Google Scholar 

  166. Kuo MC, Liang DC, Huang CF, Shih YS, Wu JH, Lin TL et al. RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutations at the C-terminal region might predict acute myeloid leukemia transformation. Leukemia 2009; 23: 1426–1431.

    CAS  PubMed  Google Scholar 

  167. Slattery ML, Lundgreen A, Herrick JS, Caan BJ, Potter JD, Wolff RK . Associations between genetic variation in RUNX1, RUNX2, RUNX3, MAPK1 and eIF4E and riskof colon and rectal cancer: additional support for a TGF-beta-signaling pathway. Carcinogenesis 2011; 32: 318–326.

    CAS  PubMed  Google Scholar 

  168. Fijneman RJ, Anderson RA, Richards E, Liu J, Tijssen M, Meijer GA et al. Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract. Cancer Sci 2012; 103: 593–599.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Sakakura C, Hagiwara A, Miyagawa K, Nakashima S, Yoshikawa T, Kin S et al. Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer. Int J Cancer 2005; 113: 221–228.

    CAS  PubMed  Google Scholar 

  170. Wu C, Hu Z, He Z, Jia W, Wang F, Zhou Y et al. Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations. Nat Genet 2011; 43: 679–684.

    CAS  PubMed  Google Scholar 

  171. Boonstra JJ, van Marion R, Douben HJ, Lanchbury JS, Timms KM, Abkevich V et al. Mapping of homozygous deletions in verified esophageal adenocarcinoma cell lines and xenografts. Genes Chromosomes Cancer 2012; 51: 272–282.

    CAS  PubMed  Google Scholar 

  172. Huang SP, Lan YH, Lu TL, Pao JB, Chang TY, Lee HZ et al. Clinical significance of runt-related transcription factor 1 polymorphism in prostate cancer. BJU Int 2011; 107: 486–492.

    CAS  PubMed  Google Scholar 

  173. Thomas DM, Johnson SA, Sims NA, Trivett MK, Slavin JL, Rubin BP et al. Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma. J Cell Biol 2004; 167: 925–934.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Martin JW, Zielenska M, Stein GS, van Wijnen AJ, Squire JA . The role of RUNX2 in osteosarcoma oncogenesis. Sarcoma 2011; 2011: 282745.

    CAS  PubMed  Google Scholar 

  175. Ito K, Liu Q, Salto-Tellez M, Yano T, Tada K, Ida H et al. RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization. Cancer Res 2005; 65: 7743–7750.

    CAS  PubMed  Google Scholar 

  176. Lee SH, Kim J, Kim WH, Lee YM . Hypoxic silencing of tumor suppressor RUNX3 by histone modification in gastric cancer cells. Oncogene 2009; 28: 184–194.

    PubMed  Google Scholar 

  177. Oshimo Y, Oue N, Mitani Y, Nakayama H, Kitadai Y, Yoshida K et al. Frequent loss of RUNX3 expression by promoter hypermethylation in gastric carcinoma. Pathobiology 2004; 71: 137–143.

    CAS  PubMed  Google Scholar 

  178. Kim WJ, Kim EJ, Jeong P, Quan C, Kim J, Li QL et al. RUNX3 inactivation by point mutations and aberrant DNA methylation in bladder tumors. Cancer Res 2005; 65: 9347–9354.

    CAS  PubMed  Google Scholar 

  179. Wolff EM, Liang G, Cortez CC, Tsai YC, Castelao JE, Cortessis VK et al. RUNX3 methylation reveals that bladder tumors are older in patients with a history of smoking. Cancer Res 2008; 68: 6208–6214.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Yan C, Kim YW, Ha YS, Kim IY, Kim YJ, Yun SJ et al. RUNX3 methylation as a predictor for disease progression in patients with non-muscle-invasive bladder cancer. J Surg Oncol 2012; 105: 425–430.

    CAS  PubMed  Google Scholar 

  181. Richiardi L, Fiano V, Vizzini L, De Marco L, Delsedime L, Akre O et al. Promoter methylation in APC, RUNX3, and GSTP1 and mortality in prostate cancer patients. J Clin Oncol 2009; 27: 3161–3168.

    CAS  PubMed  Google Scholar 

  182. Sato K, Tomizawa Y, Iijima H, Saito R, Ishizuka T, Nakajima T et al. Epigenetic inactivation of the RUNX3 gene in lung cancer. Oncol Rep 2006; 15: 129–135.

    CAS  PubMed  Google Scholar 

  183. Wada M, Yazumi S, Takaishi S, Hasegawa K, Sawada M, Tanaka H et al. Frequent loss of RUNX3 gene expression in human bile duct and pancreatic cancer cell lines. Oncogene 2004; 23: 2401–2407.

    CAS  PubMed  Google Scholar 

  184. Ahlquist T, Lind GE, Costa VL, Meling GI, Vatn M, Hoff GS et al. Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers. Mol Cancer 2008; 7: 94.

    PubMed  PubMed Central  Google Scholar 

  185. Subramaniam MM, Chan JY, Soong R, Ito K, Yeoh KG, Wong R et al. RUNX3 inactivation in colorectal polyps arising through different pathways of colonic carcinogenesis. Am J Gastroenterol 2009; 104: 426–436.

    CAS  PubMed  Google Scholar 

  186. Soong R, Shah N, Peh BK, Chong PY, Ng SS, Zeps N et al. The expression of RUNX3 in colorectal cancer is associated with disease stage and patient outcome. Br J Cancer 2009; 100: 676–679.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Ito K, Lim AC, Salto-Tellez M, Motoda L, Osato M, Chuang LS et al. RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis. Cancer Cell 2008; 14: 226–237.

    CAS  PubMed  Google Scholar 

  188. Mueller W, Nutt CL, Ehrich M, Riemenschneider MJ, von Deimling A, van den Boom D et al. Downregulation of RUNX3 and TES by hypermethylation in glioblastoma. Oncogene 2007; 26: 583–593.

    CAS  PubMed  Google Scholar 

  189. Gao F, Huang C, Lin M, Wang Z, Shen J, Zhang H et al. Frequent inactivation of RUNX3 by promoter hypermethylation and protein mislocalization in oral squamous cell carcinomas. J Cancer Res Clinical Oncol 2009; 135: 739–747.

    CAS  Google Scholar 

  190. Shiraha H, Nishina S, Yamamoto K . Loss of runt-related transcription factor 3 causes development and progression of hepatocellular carcinoma. J Cell Biochem 2011; 112: 745–749.

    CAS  PubMed  Google Scholar 

  191. He L, Zhao X, Wang H, Zhang P, Guo C, Huang C et al. RUNX3 Mediates Suppression of Tumor Growth and Metastasis of Human CCRCC by Regulating Cyclin Related Proteins and TIMP-1. PLoS One 2012; 7: 3.

    Google Scholar 

  192. Han YX, Liang DY . The role of the tumor suppressor RUNX3 in giant cell tumor of the bone. Int J Oncol 2012; 40: 673–678.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Gerhard A Coetzee, Debu Tripathy, Gillian H Little (University of Southern California) and Andre van Wijnen (University of Massachusetts Medical School) for carefully reading the manuscript and providing critical comments. We are particularly thankful to Charles Perou (University of North Carolina), Dan Koboldt and Matthew Ellis (Washington University), who also shared, analyzed and edited data for this review. This work was supported by NIH grant R01 DK071122 from the National Institute of Diabetes and Digestive and Kidney Diseases to BF, who holds the J Harold and Edna L LaBriola Chair in Genetic Orthopaedic Research at USC.

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  1. Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    N-O Chimge

  2. Departments of Orthopaedic Surgery and Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    B Frenkel

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Chimge, NO., Frenkel, B. The RUNX family in breast cancer: relationships with estrogen signaling. Oncogene 32, 2121–2130 (2013). https://doi.org/10.1038/onc.2012.328

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