Browse > Article
http://dx.doi.org/10.14348/molcells.2019.0310

Complex Interplay between the RUNX Transcription Factors and Wnt/β-Catenin Pathway in Cancer: A Tango in the Night  

Sweeney, Kerri (CRUK Beatson Institute, Garscube Estate)
Cameron, Ewan R. (Glasgow Veterinary School, University of Glasgow)
Blyth, Karen (CRUK Beatson Institute, Garscube Estate)
Abstract
Cells are designed to be sensitive to a myriad of external cues so they can fulfil their individual destiny as part of the greater whole. A number of well-characterised signalling pathways dictate the cell's response to the external environment and incoming messages. In healthy, well-ordered homeostatic systems these signals are tightly controlled and kept in balance. However, given their powerful control over cell fate, these pathways, and the transcriptional machinery they orchestrate, are frequently hijacked during the development of neoplastic disease. A prime example is the Wnt signalling pathway that can be modulated by a variety of ligands and inhibitors, ultimately exerting its effects through the β-catenin transcription factor and its downstream target genes. Here we focus on the interplay between the three-member family of RUNX transcription factors with the Wnt pathway and how together they can influence cell behaviour and contribute to cancer development. In a recurring theme with other signalling systems, the RUNX genes and the Wnt pathway appear to operate within a series of feedback loops. RUNX genes are capable of directly and indirectly regulating different elements of the Wnt pathway to either strengthen or inhibit the signal. Equally, β-catenin and its transcriptional co-factors can control RUNX gene expression and together they can collaborate to regulate a large number of third party co-target genes.
Keywords
cancer; RUNX1; RUNX2; RUNX3; Wnt; ${\beta}$-catenin;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Chimge, N.O., Little, G.H., Baniwal, S.K., Adisetiyo, H., Xie, Y., Zhang, T., O'Laughlin, A., Liu, Z.Y., Ulrich, P., Martin, A., et al. (2016). RUNX1 prevents oestrogen-mediated AXIN1 suppression and beta-catenin activation in ER-positive breast cancer. Nat. Commun. 7, 10751.   DOI
2 Choi, A., Illendula, A., Pulikkan, J.A., Roderick, J.E., Tesell, J., Yu, J., Hermance, N., Zhu, L.J., Castilla, L.H., Bushweller, J.H., et al. (2017). RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia. Blood 130, 1722-1733.   DOI
3 Chuang, L.S., Ito, K., and Ito, Y. (2017). Roles of RUNX in solid tumors. Adv. Exp. Med. Biol. 962, 299-320.   DOI
4 Clements, W.M., Wang, J., Sarnaik, A., Kim, O.J., MacDonald, J., Fenoglio- Preiser, C., Groden, J., and Lowy, A.M. (2002). beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res. 62, 3503-3506.
5 Clevers, H. (2000). Axin and hepatocellular carcinomas. Nat. Genet. 24, 206-208.   DOI
6 Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell 127, 469-480.   DOI
7 Ferrari, N., Riggio, A.I., Mason, S., McDonald, L., King, A., Higgins, T., Rosewell, I., Neil, J.C., Smalley, M.J., Sansom, O.J., et al. (2015). Runx2 contributes to the regenerative potential of the mammary epithelium. Sci. Rep. 5, 15658.   DOI
8 Fiedler, M., Graeb, M., Mieszczanek, J., Rutherford, T.J., Johnson, C.M., and Bienz, M. (2015). An ancient Pygo-dependent Wnt enhanceosome integrated by Chip/LDB-SSDP. eLife 4, e09073.   DOI
9 Fijneman, R.J., Anderson, R.A., Richards, E., Liu, J., Tijssen, M., Meijer, G.A., Anderson, J., Rod, A., O'Sullivan, M.G., Scott, P.M., et al. (2012). Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract. Cancer Sci. 103, 593-599.   DOI
10 Friedman, A.D. (2009). Cell cycle and developmental control of hematopoiesis by Runx1. J. Cell. Physiol. 219, 520-524.   DOI
11 Fu, Y., Sun, S., Man, X., and Kong, C. (2019). Increased expression of RUNX1 in clear cell renal cell carcinoma predicts poor prognosis. PeerJ 7, e7854.   DOI
12 Grigoryan, T., Wend, P., Klaus, A., and Birchmeier, W. (2008). Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes Dev. 22, 2308-2341.   DOI
13 Goldsberry, W.N., Londono, A., Randall, T.D., Norian, L.A., and Arend, R.C. (2019). A review of the role of Wnt in cancer immunomodulation. Cancers 11, E771.   DOI
14 Goyama, S., Schibler, J., Cunningham, L., Zhang, Y., Rao, Y., Nishimoto, N., Nakagawa, M., Olsson, A., Wunderlich, M., Link, K.A., et al. (2013). Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells. J. Clin. Invest. 123, 3876-3888.   DOI
15 Gregorieff, A., Stange, D.E., Kujala, P., Begthel, H., van den Born, M., Korving, J., Peters, P.J., and Clevers, H. (2009). The ets-domain transcription factor Spdef promotes maturation of goblet and paneth cells in the intestinal epithelium. Gastroenterology 137, 1333-1345.e1-e3.   DOI
16 Haxaire, C., Hay, E., and Geoffroy, V. (2016). Runx2 controls bone resorption through the down-regulation of the Wnt pathway in osteoblasts. Am. J. Pathol. 186, 1598-1609.   DOI
17 Hoeppner, L.H., Secreto, F., Jensen, E.D., Li, X., Kahler, R.A., and Westendorf, J.J. (2009). Runx2 and bone morphogenic protein 2 regulate the expression of an alternative Lef1 transcript during osteoblast maturation. J. Cell. Physiol. 221, 480-489.   DOI
18 Wu, J.Q., Seay, M., Schulz, V.P., Hariharan, M., Tuck, D., Lian, J., Du, J., Shi, M., Ye, Z., Gerstein, M., et al. (2012). Tcf7 is an important regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line. PLoS Genet. 8, e1002565.   DOI
19 Whittle, M.C. and Hingorani, S.R. (2017). Runx3 and cell fate decisions in pancreas cancer. Adv. Exp. Med. Biol. 962, 333-352.   DOI
20 Whittle, M.C., Izeradjene, K., Rani, P.G., Feng, L., Carlson, M.A., DelGiorno, K.E., Wood, L.D., Goggins, M., Hruban, R.H., Chang, A.E., et al. (2015). RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma. Cell 161, 1345-1360.   DOI
21 Xiao, W.H. and Liu, W.W. (2004). Hemizygous deletion and hypermethylation of RUNX3 gene in hepatocellular carcinoma. World J. Gastroenterol. 10, 376-380.   DOI
22 Zhan, T., Rindtorff, N., and Boutros, M. (2017). Wnt signaling in cancer. Oncogene 36, 1461-1473.   DOI
23 Zhang, Z., Cheng, L., Li, J., Farah, E., Atallah, N.M., Pascuzzi, P.E., Gupta, S., and Liu, X. (2018). Inhibition of the Wnt/beta-catenin pathway overcomes resistance to enzalutamide in castration-resistant prostate cancer. Cancer Res. 78, 3147-3162.   DOI
24 Blyth, K., Cameron, E.R., and Neil, J.C. (2005). The RUNX genes: gain or loss of function in cancer. Nat. Rev. Cancer 5, 376-387.   DOI
25 Barnes, G.L., Hebert, K.E., Kamal, M., Javed, A., Einhorn, T.A., Lian, J.B., Stein, G.S., and Gerstenfeld, L.C. (2004). Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastases-associated osteolytic disease. Cancer Res. 64, 4506-4513.   DOI
26 Barnes, G.L., Javed, A., Waller, S.M., Kamal, M.H., Hebert, K.E., Hassan, M.Q., Bellahcene, A., Van Wijnen, A.J., Young, M.F., Lian, J.B., et al. (2003). Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells. Cancer Res. 63, 2631-2637.
27 Ben-Ami, O., Friedman, D., Leshkowitz, D., Goldenberg, D., Orlovsky, K., Pencovich, N., Lotem, J., Tanay, A., and Groner, Y. (2013). Addiction of t(8;21) and inv(16) acute myeloid leukemia to native RUNX1. Cell Rep. 4, 1131-1143.   DOI
28 Bocchinfuso, W.P., Hively, W.P., Couse, J.F., Varmus, H.E., and Korach, K.S. (1999). A mouse mammary tumor virus-Wnt-1 transgene induces mammary gland hyperplasia and tumorigenesis in mice lacking estrogen receptor-alpha. Cancer Res. 59, 1869-1876.
29 Brenner, O., Levanon, D., Negreanu, V., Golubkov, O., Fainaru, O., Woolf, E., and Groner, Y. (2004). Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia. Proc. Natl. Acad. Sci. U. S. A. 101, 16016-16021.   DOI
30 Bushweller, J.H. (2019). Targeting transcription factors in cancer - from undruggable to reality. Nat. Rev. Cancer 19, 611-624.   DOI
31 Araki, K., Osaki, M., Nagahama, Y., Hiramatsu, T., Nakamura, H., Ohgi, S., and Ito, H. (2005). Expression of RUNX3 protein in human lung adenocarcinoma: implications for tumor progression and prognosis. Cancer Sci. 96, 227-231.   DOI
32 Akech, J., Wixted, J.J., Bedard, K., van der Deen, M., Hussain, S., Guise, T.A., van Wijnen, A.J., Stein, J.L., Languino, L.R., Altieri, D.C., et al. (2010). Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene 29, 811-821.   DOI
33 Anastas, J.N. and Moon, R.T. (2013). WNT signalling pathways as therapeutic targets in cancer. Nat. Rev. Cancer 13, 11-26.   DOI
34 Andreu, P., Peignon, G., Slomianny, C., Taketo, M.M., Colnot, S., Robine, S., Lamarque, D., Laurent-Puig, P., Perret, C., and Romagnolo, B. (2008). A genetic study of the role of the Wnt/beta-catenin signalling in Paneth cell differentiation. Dev. Biol. 324, 288-296.   DOI
35 van der Horst, S.E.M., Cravo, J., Woollard, A., Teapal, J., and van den Heuvel, S. (2019). C. elegans Runx/CBF$\beta$ suppresses POP-1 TCF to convert asymmetric to proliferative division of stem cell-like seam cells. Development 146, dev.180034.   DOI
36 Wang, B., Tian, T., Kalland, K.H., Ke, X., and Qu, Y. (2018). Targeting Wnt/beta-catenin signaling for cancer immunotherapy. Trends Pharmacol. Sci. 39, 648-658.   DOI
37 Wang, J., Sinha, T., and Wynshaw-Boris, A. (2012). Wnt signaling in mammalian development: lessons from mouse genetics. Cold Spring Harb. Perspect. Biol. 4, a007963.   DOI
38 Cai, T., Sun, D., Duan, Y., Wen, P., Dai, C., Yang, J., and He, W. (2016). WNT/beta-catenin signaling promotes VSMCs to osteogenic transdifferentiation and calcification through directly modulating Runx2 gene expression. Exp. Cell Res. 345, 206-217.   DOI
39 Banerji, S., Cibulskis, K., Rangel-Escareno, C., Brown, K.K., Carter, S.L., Frederick, A.M., Lawrence, M.S., Sivachenko, A.Y., Sougnez, C., Zou, L., et al. (2012). Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405-409.   DOI
40 Barker, N. and Clevers, H. (2006). Mining the Wnt pathway for cancer therapeutics. Nat. Rev. Drug Discov. 5, 997-1014.   DOI
41 Cancer Genome Atlas Network (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330-337.   DOI
42 Cerami, E., Gao, J., Dogrusoz, U., Gross, B.E., Sumer, S.O., Aksoy, B.A., Jacobsen, A., Byrne, C.J., Heuer, M.L., Larsson, E., et al. (2012). The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401-404.   DOI
43 Cheng, C.K., Li, L., Cheng, S.H., Ng, K., Chan, N.P., Ip, R.K., Wong, R.S., Shing, M.M., Li, C.K., and Ng, M.H. (2011). Secreted-frizzled related protein 1 is a transcriptional repression target of the t(8;21) fusion protein in acute myeloid leukemia. Blood 118, 6638-6648.   DOI
44 Cheng, X., Xu, X., Chen, D., Zhao, F., and Wang, W. (2019). Therapeutic potential of targeting the Wnt/beta-catenin signaling pathway in colorectal cancer. Biomed. Pharmacother. 110, 473-481.   DOI
45 Chimge, N.O., Ahmed-Alnassar, S., and Frenkel, B. (2017). Relationship between RUNX1 and AXIN1 in ER-negative versus ER-positive breast cancer. Cell Cycle 16, 312-318.   DOI
46 Chimge, N.O., Baniwal, S.K., Little, G.H., Chen, Y.B., Kahn, M., Tripathy, D., Borok, Z., and Frenkel, B. (2011). Regulation of breast cancer metastasis by Runx2 and estrogen signaling: the role of SNAI2. Breast Cancer Res. 13, R127.   DOI
47 Ito, K., Liu, Q., Salto-Tellez, M., Yano, T., Tada, K., Ida, H., Huang, C., Shah, N., Inoue, M., Rajnakova, A., et al. (2005). RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization. Cancer Res. 65, 7743-7750.   DOI
48 Illendula, A., Gilmour, J., Grembecka, J., Tirumala, V.S.S., Boulton, A., Kuntimaddi, A., Schmidt, C., Wang, L., Pulikkan, J.A., Zong, H., et al. (2016). Small molecule inhibitor of CBFbeta-RUNX binding for RUNX transcription factor driven cancers. EBioMedicine 8, 117-131.   DOI
49 Ito, K., Chuang, L.S., Ito, T., Chang, T.L., Fukamachi, H., Salto-Tellez, M., and Ito, Y. (2011). Loss of Runx3 is a key event in inducing precancerous state of the stomach. Gastroenterology 140, 1536-1546.e8.   DOI
50 Ito, K., Lim, A.C., Salto-Tellez, M., Motoda, L., Osato, M., Chuang, L.S., Lee, C.W., Voon, D.C., Koo, J.K., Wang, H., et al. (2008). RUNX3 attenuates betacatenin/T cell factors in intestinal tumorigenesis. Cancer Cell 14, 226-237.   DOI
51 Ito, Y., Bae, S.C., and Chuang, L.S. (2015). The RUNX family: developmental regulators in cancer. Nat. Rev. Cancer 15, 81-95.   DOI
52 Jain, P., Nattakom, M., Holowka, D., Wang, D.H., Thomas Brenna, J., Ku, A.T., Nguyen, H., Ibrahim, S.F., and Tumbar, T. (2018). Runx1 role in epithelial and cancer cell proliferation implicates lipid metabolism and Scd1 and Soat1 activity. Stem Cells 36, 1603-1616.   DOI
53 James, M.J., Jarvinen, E., Wang, X.P., and Thesleff, I. (2006). Different roles of Runx2 during early neural crest-derived bone and tooth development. J. Bone Miner. Res. 21, 1034-1044.   DOI
54 Jarvinen, E., Shimomura-Kuroki, J., Balic, A., Jussila, M., and Thesleff, I. (2018). Mesenchymal Wnt/beta-catenin signaling limits tooth number. Development 145, dev158048.   DOI
55 Ellis, M.J., Ding, L., Shen, D., Luo, J., Suman, V.J., Wallis, J.W., Van Tine, B.A., Hoog, J., Goiffon, R.J., Goldstein, T.C., et al. (2012). Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486, 353- 360.   DOI
56 Cui, C., Zhou, X., Zhang, W., Qu, Y., and Ke, X. (2018). Is beta-catenin a druggable target for cancer therapy? Trends Biochem. Sci. 43, 623-634.   DOI
57 Dalle Carbonare, L., Frigo, A., Francia, G., Davi, M.V., Donatelli, L., Stranieri, C., Brazzarola, P., Zatelli, M.C., Menestrina, F., and Valenti, M.T. (2012). Runx2 mRNA expression in the tissue, serum, and circulating nonhematopoietic cells of patients with thyroid cancer. J. Clin. Endocrinol. Metab. 97, E1249-1256.   DOI
58 De Braekeleer, E., Ferec, C., and De Braekeleer, M. (2009). RUNX1 translocations in malignant hemopathies. Anticancer Res. 29, 1031-1037.
59 Dey, N., Barwick, B.G., Moreno, C.S., Ordanic-Kodani, M., Chen, Z., Oprea-Ilies, G., Tang, W., Catzavelos, C., Kerstann, K.F., Sledge, G.W., Jr., et al. (2013). Wnt signaling in triple negative breast cancer is associated with metastasis. BMC Cancer 13, 537.   DOI
60 Dong, Y.F., Soung do, Y., Schwarz, E.M., O'Keefe, R.J., and Drissi, H. (2006). Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor. J. Cell. Physiol. 208, 77-86.   DOI
61 Endo, T., Ohta, K., and Kobayashi, T. (2008). Expression and function of Cbfa-1/Runx2 in thyroid papillary carcinoma cells. J. Clin. Endocrinol. Metab. 93, 2409-2412.   DOI
62 Perez-Campo, F.M., Santurtun, A., Garcia-Ibarbia, C., Pascual, M.A., Valero, C., Garces, C., Sanudo, C., Zarrabeitia, M.T., and Riancho, J.A. (2016). Osterix and RUNX2 are transcriptional regulators of sclerostin in human bone. Calcif. Tissue Int. 99, 302-309.   DOI
63 Gao, J., Aksoy, B.A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S.O., Sun, Y., Jacobsen, A., Sinha, R., Larsson, E., et al. (2013). Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1.
64 Gaur, T., Lengner, C.J., Hovhannisyan, H., Bhat, R.A., Bodine, P.V., Komm, B.S., Javed, A., van Wijnen, A.J., Stein, J.L., Stein, G.S., et al. (2005). Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J. Biol. Chem. 280, 33132-33140.   DOI
65 Okuda, T., van Deursen, J., Hiebert, S.W., Grosveld, G., and Downing, J.R. (1996). AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321-330.   DOI
66 Osato, M. (2004). Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia. Oncogene 23, 4284-4296.   DOI
67 Osorio, K.M., Lilja, K.C., and Tumbar, T. (2011). Runx1 modulates adult hair follicle stem cell emergence and maintenance from distinct embryonic skin compartments. J. Cell Biol. 193, 235-250.   DOI
68 Otto, F., Thornell, A.P., Crompton, T., Denzel, A., Gilmour, K.C., Rosewell, I.R., Stamp, G.W., Beddington, R.S., Mundlos, S., Olsen, B.R., et al. (1997). Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765-771.   DOI
69 Owens, T.W., Rogers, R.L., Best, S., Ledger, A., Mooney, A.M., Ferguson, A., Shore, P., Swarbrick, A., Ormandy, C.J., Simpson, P.T., et al. (2014). Runx2 is a novel regulator of mammary epithelial cell fate in development and breast cancer. Cancer Res. 74, 5277-5286.   DOI
70 Ju, X., Ishikawa, T.O., Naka, K., Ito, K., Ito, Y., and Oshima, M. (2014). Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells. Cancer Sci. 105, 418-424.   DOI
71 Kahler, R.A. and Westendorf, J.J. (2003). Lymphoid enhancer factor-1 and beta-catenin inhibit Runx2-dependent transcriptional activation of the osteocalcin promoter. J. Biol. Chem. 278, 11937-11944.   DOI
72 Kawane, T., Komori, H., Liu, W., Moriishi, T., Miyazaki, T., Mori, M., Matsuo, Y., Takada, Y., Izumi, S., Jiang, Q., et al. (2014). Dlx5 and mef2 regulate a novel runx2 enhancer for osteoblast-specific expression. J. Bone Miner. Res. 29, 1960-1969.   DOI
73 Khramtsov, A.I., Khramtsova, G.F., Tretiakova, M., Huo, D., Olopade, O.I., and Goss, K.H. (2010). Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am. J. Pathol. 176, 2911-2920.   DOI
74 Kim, M.S., Gernapudi, R., Choi, E.Y., Lapidus, R.G., and Passaniti, A. (2017). Characterization of CADD522, a small molecule that inhibits RUNX2-DNA binding and exhibits antitumor activity. Oncotarget 8, 70916-70940.   DOI
75 Kinzler, K.W., Nilbert, M.C., Su, L.K., Vogelstein, B., Bryan, T.M., Levy, D.B., Smith, K.J., Preisinger, A.C., Hedge, P., McKechnie, D., et al. (1991). Identification of FAP locus genes from chromosome 5q21. Science 253, 661-665.   DOI
76 Riggio, A.I. and Blyth, K. (2017). The enigmatic role of RUNX1 in femalerelated cancers - current knowledge & future perspectives. FEBS J. 284, 2345-2362.   DOI
77 Pratap, J., Lian, J.B., Javed, A., Barnes, G.L., van Wijnen, A.J., Stein, J.L., and Stein, G.S. (2006). Regulatory roles of Runx2 in metastatic tumor and cancer cell interactions with bone. Cancer Metastasis Rev. 25, 589-600.   DOI
78 Qin, X., Jiang, Q., Miyazaki, T., and Komori, T. (2019). Runx2 regulates cranial suture closure by inducing hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in suture mesenchymal cells. Hum. Mol. Genet. 28, 896-911.   DOI
79 Reinhold, M.I. and Naski, M.C. (2007). Direct interactions of Runx2 and canonical Wnt signaling induce FGF18. J. Biol. Chem. 282, 3653-3663.   DOI
80 Rooney, N., Riggio, A.I., Mendoza-Villanueva, D., Shore, P., Cameron, E.R., and Blyth, K. (2017). Runx genes in breast cancer and the mammary lineage. Adv. Exp. Med. Biol. 962, 353-368.   DOI
81 Lee, Y.S., Lee, J.W., Jang, J.W., Chi, X.Z., Kim, J.H., Li, Y.H., Kim, M.K., Kim, D.M., Choi, B.S., Kim, E.G., et al. (2013). Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma. Cancer Cell 24, 603-616.   DOI
82 Komori, T., Yagi, H., Nomura, S., Yamaguchi, A., Sasaki, K., Deguchi, K., Shimizu, Y., Bronson, R.T., Gao, Y.H., Inada, M., et al. (1997). Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755-764.   DOI
83 Korinek, V., Barker, N., Morin, P.J., van Wichen, D., de Weger, R., Kinzler, K.W., Vogelstein, B., and Clevers, H. (1997). Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 275, 1784-1787.   DOI
84 Rubinfeld, B., Albert, I., Porfiri, E., Munemitsu, S., and Polakis, P. (1997). Loss of beta-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene. Cancer Res. 57, 4624-4630.
85 Rubinfeld, B., Souza, B., Albert, I., Muller, O., Chamberlain, S.H., Masiarz, F.R., Munemitsu, S., and Polakis, P. (1993). Association of the APC gene product with beta-catenin. Science 262, 1731-1734.   DOI
86 Sadikovic, B., Thorner, P., Chilton-Macneill, S., Martin, J.W., Cervigne, N.K., Squire, J., and Zielenska, M. (2010). Expression analysis of genes associated with human osteosarcoma tumors shows correlation of RUNX2 overexpression with poor response to chemotherapy. BMC Cancer 10, 202.   DOI
87 Kugimiya, F., Kawaguchi, H., Ohba, S., Kawamura, N., Hirata, M., Chikuda, H., Azuma, Y., Woodgett, J.R., Nakamura, K., and Chung, U.I. (2007). GSK- 3beta controls osteogenesis through regulating Runx2 activity. PLoS One 2, e837.   DOI
88 Kurek, K.C., Del Mare, S., Salah, Z., Abdeen, S., Sadiq, H., Lee, S.H., Gaudio, E., Zanesi, N., Jones, K.B., DeYoung, B., et al. (2010). Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression. Cancer Res. 70, 5577-5586.   DOI
89 Levanon, D., Bettoun, D., Harris-Cerruti, C., Woolf, E., Negreanu, V., Eilam, R., Bernstein, Y., Goldenberg, D., Xiao, C., Fliegauf, M., et al. (2002). The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons. EMBO J. 21, 3454-3463.   DOI
90 Li, Q., Lai, Q., He, C., Fang, Y., Yan, Q., Zhang, Y., Wang, X., Gu, C., Wang, Y., Ye, L., et al. (2019). RUNX1 promotes tumour metastasis by activating the Wnt/beta-catenin signalling pathway and EMT in colorectal cancer. J. Exp. Clin. Cancer Res. 38, 334.   DOI
91 Li, Q.L., Ito, K., Sakakura, C., Fukamachi, H., Inoue, K., Chi, X.Z., Lee, K.Y., Nomura, S., Lee, C.W., Han, S.B., et al. (2002). Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109, 113-124.   DOI
92 Segditsas, S. and Tomlinson, I. (2006). Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25, 7531-7537.   DOI
93 Sato, K., Tomizawa, Y., Iijima, H., Saito, R., Ishizuka, T., Nakajima, T., and Mori, M. (2006). Epigenetic inactivation of the RUNX3 gene in lung cancer. Oncol. Rep. 15, 129-135.
94 Satoh, S., Daigo, Y., Furukawa, Y., Kato, T., Miwa, N., Nishiwaki, T., Kawasoe, T., Ishiguro, H., Fujita, M., Tokino, T., et al. (2000). AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat. Genet. 24, 245-250.   DOI
95 Scheitz, C.J. and Tumbar, T. (2013). New insights into the role of Runx1 in epithelial stem cell biology and pathology. J. Cell. Biochem. 114, 985-993.   DOI
96 Shiraha, H., Nishina, S., and Yamamoto, K. (2011). Loss of runt-related transcription factor 3 causes development and progression of hepatocellular carcinoma. J. Cell. Biochem. 112, 745-749.   DOI
97 Speidel, D., Wellbrock, J., and Abas, M. (2017). RUNX1 upregulation by cytotoxic drugs promotes apoptosis. Cancer Res. 77, 6818-6824.   DOI
98 Su, L.K., Vogelstein, B., and Kinzler, K.W. (1993). Association of the APC tumor suppressor protein with catenins. Science 262, 1734-1737.   DOI
99 Li, S., Li, S., Sun, Y., and Li, L. (2014). The expression of beta-catenin in different subtypes of breast cancer and its clinical significance. Tumour Biol. 35, 7693-7698.   DOI
100 Steinhart, Z. and Angers, S. (2018). Wnt signaling in development and tissue homeostasis. Development 145, dev146589.   DOI
101 Sun, J., Li, B., Jia, Z., Zhang, A., Wang, G., Chen, Z., Shang, Z., Zhang, C., Cui, J., and Yang, W. (2018). RUNX3 inhibits glioma survival and invasion via suppression of the beta-catenin/TCF-4 signaling pathway. J. Neurooncol. 140, 15-26.   DOI
102 Lotem, J., Levanon, D., Negreanu, V., Bauer, O., Hantisteanu, S., Dicken, J., and Groner, Y. (2015). Runx3 at the interface of immunity, inflammation and cancer. Biochim. Biophys. Acta 1855, 131-143.
103 Lian, R., Ma, H., Wu, Z., Zhang, G., Jiao, L., Miao, W., Jin, Q., Li, R., Chen, P., Shi, H., et al. (2018). EZH2 promotes cell proliferation by regulating the expression of RUNX3 in laryngeal carcinoma. Mol. Cell. Biochem. 439, 35-43.   DOI
104 Lie-a-ling, M., Mevel, R., Patel, R., Blyth, K., Baena, E., Kouskoff, V., and Lacaud, G. (2020). RUNX1 dosage in development and cancer. Mol. Cells 43, 126-138.   DOI
105 Lin, S.Y., Xia, W., Wang, J.C., Kwong, K.Y., Spohn, B., Wen, Y., Pestell, R.G., and Hung, M.C. (2000). Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc. Natl. Acad. Sci. U. S. A. 97, 4262-4266.   DOI
106 Lotem, J., Levanon, D., Negreanu, V., Bauer, O., Hantisteanu, S., Dicken, J., and Groner, Y. (2017). Runx3 in immunity, inflammation and cancer. Adv. Exp. Med. Biol. 962, 369-393.   DOI
107 Luis, T.C., Ichii, M., Brugman, M.H., Kincade, P., and Staal, F.J. (2012). Wnt signaling strength regulates normal hematopoiesis and its deregulation is involved in leukemia development. Leukemia 26, 414-421.   DOI
108 Luo, Y., Zhang, Y., Miao, G., Zhang, Y., Liu, Y., and Huang, Y. (2019). Runx1 regulates osteogenic differentiation of BMSCs by inhibiting adipogenesis through Wnt/beta-catenin pathway. Arch. Oral Biol. 97, 176-184.   DOI
109 Tang, N., Song, W.X., Luo, J., Luo, X., Chen, J., Sharff, K.A., Bi, Y., He, B.C., Huang, J.Y., Zhu, G.H., et al. (2009). BMP-9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/beta-catenin signalling. J. Cell. Mol. Med. 13, 2448-2464.   DOI
110 Tanaka, S., Shiraha, H., Nakanishi, Y., Nishina, S., Matsubara, M., Horiguchi, S., Takaoka, N., Iwamuro, M., Kataoka, J., Kuwaki, K., et al. (2012). Runtrelated transcription factor 3 reverses epithelial-mesenchymal transition in hepatocellular carcinoma. Int. J. Cancer 131, 2537-2546.   DOI
111 Taniuchi, I., Osato, M., and Ito, Y. (2012). Runx1: no longer just for leukemia. EMBO J. 31, 4098-4099.   DOI
112 Tsukamoto, A.S., Grosschedl, R., Guzman, R.C., Parslow, T., and Varmus, H.E. (1988). Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55, 619-625.   DOI
113 Ugarte, G.D., Vargas, M.F., Medina, M.A., Leon, P., Necunir, D., Elorza, A.A., Gutierrez, S.E., Moon, R.T., Loyola, A., and De Ferrari, G.V. (2015). Wnt signaling induces transcription, spatial proximity, and translocation of fusion gene partners in human hematopoietic cells. Blood 126, 1785-1789.
114 Mevel, R., Draper, J.E., Lie-a-Ling, M., Kouskoff, V., and Lacaud, G. (2019). RUNX transcription factors: orchestrators of development. Development 146, dev148296.   DOI
115 Martin, J.W., Zielenska, M., Stein, G.S., van Wijnen, A.J., and Squire, J.A. (2011). The role of RUNX2 in osteosarcoma oncogenesis. Sarcoma 2011, 282745.   DOI
116 Mayall, T.P., Sheridan, P.L., Montminy, M.R., and Jones, K.A. (1997). Distinct roles for P-CREB and LEF-1 in TCR alpha enhancer assembly and activation on chromatin templates in vitro. Genes Dev. 11, 887-899.   DOI
117 McDonald, L., Ferrari, N., Terry, A., Bell, M., Mohammed, Z.M., Orange, C., Jenkins, A., Muller, W.J., Gusterson, B.A., Neil, J.C., et al. (2014). RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland. Dis. Model. Mech. 7, 525-534.   DOI
118 Medina, M.A., Ugarte, G.D., Vargas, M.F., Avila, M.E., Necunir, D., Elorza, A.A., Gutierrez, S.E., and De Ferrari, G.V. (2016). Alternative RUNX1 promoter regulation by wnt/beta-catenin signaling in leukemia cells and human hematopoietic progenitors. J. Cell. Physiol. 231, 1460-1467.   DOI
119 Mendoza-Villanueva, D., Zeef, L., and Shore, P. (2011). Metastatic breast cancer cells inhibit osteoblast differentiation through the Runx2/CBFbetadependent expression of the Wnt antagonist, sclerostin. Breast Cancer Res. 13, R106.   DOI
120 Mikasa, M., Rokutanda, S., Komori, H., Ito, K., Tsang, Y.S., Date, Y., Yoshida, C.A., and Komori, T. (2011). Regulation of Tcf7 by Runx2 in chondrocyte maturation and proliferation. J. Bone Miner. Metab. 29, 291-299.   DOI
121 Novellasdemunt, L., Antas, P., and Li, V.S. (2015). Targeting Wnt signaling in colorectal cancer. A review in the theme: cell signaling: proteins, pathways and mechanisms. Am. J. Physiol. Cell Physiol. 309, C511-C521.   DOI
122 Monteiro, J., Gaspar, C., Richer, W., Franken, P.F., Sacchetti, A., Joosten, R., Idali, A., Brandao, J., Decraene, C., and Fodde, R. (2014). Cancer stemness in Wnt-driven mammary tumorigenesis. Carcinogenesis 35, 2-13.   DOI
123 Naillat, F., Yan, W., Karjalainen, R., Liakhovitskaia, A., Samoylenko, A., Xu, Q., Sun, Z., Shen, B., Medvinsky, A., Quaggin, S., et al. (2015). Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovary. Exp. Cell Res. 332, 163-178.   DOI
124 Niini, T., Kanerva, J., Vettenranta, K., Saarinen-Pihkala, U.M., and Knuutila, S. (2000). AML1 gene amplification: a novel finding in childhood acute lymphoblastic leukemia. Haematologica 85, 362-366.
125 Nishisho, I., Nakamura, Y., Miyoshi, Y., Miki, Y., Ando, H., Horii, A., Koyama, K., Utsunomiya, J., Baba, S., and Hedge, P. (1991). Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253, 665-669.   DOI
126 North, T., Gu, T.L., Stacy, T., Wang, Q., Howard, L., Binder, M., Marin-Padilla, M., and Speck, N.A. (1999). Cbfa2 is required for the formation of intraaortic hematopoietic clusters. Development 126, 2563-2575.   DOI
127 Nusse, R. and Varmus, H.E. (1982). Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31, 99-109.   DOI