The ability of Wnt ligands to initiate a signaling cascade that results in cytoplasmic stabilization of, and nuclear localization of, β-catenin underlies their ability to regulate progenitor cell differentiation. In this review, we will summarize the current knowledge of the mechanisms underlying Wnt/β-catenin signaling and how the pathway regulates normal differentiation of stem cells in the intestine, mammary gland, and prostate. We will also discuss how dysregulation of the pathway is associated with putative cancer stem cells and the potential therapeutic implications of regulating Wnt signaling.
References
[1]
Jordan, C.T.; Guzman, M.L.; Noble, M. Cancer stem cells. N Engl. J. Med. 2006, 355, 1253–1261.
[2]
Rosen, J.M.; Jordan, C.T. The increasing complexity of the cancer stem cell paradigm. Science 2009, 324, 1670–1673.
[3]
Reya, T.; Clevers, H. Wnt signalling in stem cells and cancer. Nature 2005, 434, 843–850.
[4]
Hobmayer, B.; Rentzsch, F.; Kuhn, K.; Happel, C.M.; von Laue, C.C.; Snyder, P.; Rothbacher, U.; Holstein, T.W. Wnt signalling molecules act in axis formation in the diploblastic metazoan Hydra. Nature 2000, 407, 186–189.
[5]
Batlle, E.; Bacani, J.; Begthel, H.; Jonkheer, S.; Gregorieff, A.; van de Born, M.; Malats, N.; Sancho, E.; Boon, E.; Pawson, T.; Gallinger, S.; Pals, S.; Clevers, H. EphB receptor activity suppresses colorectal cancer progression. Nature 2005, 435, 1126–1130.
[6]
Li, Y.; Hively, W.P.; Varmus, H.E. Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer. Oncogene 2000, 19, 1002–1009.
[7]
Nusse, R.; Varmus, H.E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982, 31, 99–109.
[8]
Nusslein-Volhard, C.; Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 1980, 287, 795–801.
[9]
Rijsewijk, F.; Schuermann, M.; Wagenaar, E.; Parren, P.; Weigel, D.; Nusse, R. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell 1987, 50, 649–657.
[10]
Perrimon, N.; Mahowald, A.P. Multiple functions of segment polarity genes in Drosophila. Dev. Biol. 1987, 119, 587–600.
[11]
McMahon, A.P.; Moon, R.T. Ectopic expression of the proto-oncogene int-1 in Xenopus embryos leads to duplication of the embryonic axis. Cell 1989, 58, 1075–1084.
[12]
Nusse, R.; Brown, A.; Papkoff, J.; Scambler, P.; Shackleford, G.; McMahon, A.; Moon, R.; Varmus, H. A new nomenclature for int-1 and related genes: The Wnt gene family. Cell 1991, 64, 231.
[13]
Bhanot, P.; Brink, M.; Samos, C.H.; Hsieh, J.C.; Wang, Y.; Macke, J.P.; Andrew, D.; Nathans, J.; Nusse, R. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 1996, 382, 225–230.
[14]
Sawa, H.; Lobel, L.; Horvitz, H.R. The Caenorhabditis elegans gene lin-17, which is required for certain asymmetric cell divisions, encodes a putative seven-transmembrane protein similar to the Drosophila frizzled protein. Genes Dev. 1996, 10, 2189–2197.
[15]
Yang-Snyder, J.; Miller, J.R.; Brown, J.D.; Lai, C.J.; Moon, R.T. A frizzled homolog functions in a vertebrate Wnt signaling pathway. Curr. Biol. 1996, 6, 1302–1306.
[16]
Wilson, S.I.; Rydstrom, A.; Trimborn, T.; Willert, K.; Nusse, R.; Jessell, T.M.; Edlund, T. The status of Wnt signalling regulates neural and epidermal fates in the chick embryo. Nature 2001, 411, 325–330.
[17]
Willert, K.; Brown, J.D.; Danenberg, E.; Duncan, A.W.; Weissman, I.L.; Reya, T.; Yates, J.R., 3rd; Nusse, R. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 2003, 423, 448–452.
[18]
Takada, R.; Satomi, Y.; Kurata, T.; Ueno, N.; Norioka, S.; Kondoh, H.; Takao, T.; Takada, S. Monounsaturated fatty acid modification of Wnt protein: Its role in Wnt secretion. Dev. Cell 2006, 11, 791–801.
[19]
Kadowaki, T.; Wilder, E.; Klingensmith, J.; Zachary, K.; Perrimon, N. The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing. Genes Dev. 1996, 10, 3116–3128.
[20]
Zhai, L.; Chaturvedi, D.; Cumberledge, S. Drosophila Wnt-1 undergoes a hydrophobic modification and is targeted to lipid rafts, a process that requires porcupine. J. Biol. Chem. 2004, 279, 33220–33227.
[21]
van den Heuvel, M.; Harryman-Samos, C.; Klingensmith, J.; Perrimon, N.; Nusse, R. Mutations in the segment polarity genes Wingless and porcupine impair secretion of the Wingless protein. EMBO J. 1993, 12, 5293–5302.
[22]
Banziger, C.; Soldini, D.; Schutt, C.; Zipperlen, P.; Hausmann, G.; Basler, K. Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell 2006, 125, 509–522.
[23]
Bartscherer, K.; Pelte, N.; Ingelfinger, D.; Boutros, M. Secretion of Wnt ligands requires Evi, a conserved transmembrane protein. Cell 2006, 125, 523–533.
[24]
Hausmann, G.; Banziger, C.; Basler, K. Helping Wingless take flight: How Wnt proteins are secreted. Nat. Rev. Mol. Cell Biol. 2007, 8, 331–336.
[25]
Port, F.; Kuster, M.; Herr, P.; Furger, E.; Banziger, C.; Hausmann, G.; Basler, K. Wingless secretion promotes and requires retromer-dependent cycling of Wntless. Nat. Cell Biol. 2008, 10, 178–185.
[26]
Silhankova, M.; Port, F.; Harterink, M.; Basler, K.; Korswagen, H.C. Wnt signalling requires MTM-6 and MTM-9 myotubularin lipid-phosphatase function in Wnt-producing cells. EMBO J. 2010, 29, 4094–4105.
[27]
Binari, R.C.; Staveley, B.E.; Johnson, W.A.; Godavarti, R.; Sasisekharan, R.; Manoukian, A.S. Genetic evidence that heparin-like glycosaminoglycans are involved in Wingless signaling. Development 1997, 124, 2623–2632.
[28]
Itoh, K.; Sokol, S.Y. Heparan sulfate proteoglycans are required for mesoderm formation in Xenopus embryos. Development 1994, 120, 2703–2711.
[29]
Reichsman, F.; Smith, L.; Cumberledge, S. Glycosaminoglycans can modulate extracellular localization of the Wingless protein and promote signal transduction. J. Cell Biol. 1996, 135, 819–827.
[30]
Neumann, S.; Coudreuse, D.Y.; van der Westhuyzen, D.R.; Eckhardt, E.R.; Korswagen, H.C.; Schmitz, G.; Sprong, H. Mammalian Wnt3a is released on lipoprotein particles. Traffic 2009, 10, 334–343.
[31]
Panakova, D.; Sprong, H.; Marois, E.; Thiele, C.; Eaton, S. Lipoprotein particles are required for Hedgehog and Wingless signalling. Nature 2005, 435, 58–65.
[32]
van Amerongen, R.; Nusse, R. Towards an integrated view of Wnt signaling in development. Development 2009, 136, 3205–3214.
[33]
Choi, H.Y.; Dieckmann, M.; Herz, J.; Niemeier, A. Lrp4, a novel receptor for Dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo. PLoS One 2009, 4, e7930.
[34]
Hendrickx, M.; Leyns, L. Non-conventional Frizzled ligands and Wnt receptors. Dev. Growth Differ. 2008, 50, 229–243.
[35]
Li, Y.; Pawlik, B.; Elcioglu, N.; Aglan, M.; Kayserili, H.; Yigit, G.; Percin, F.; Goodman, F.; Nurnberg, G.; Cenani, A.; Urquhart, J.; Chung, B.D.; Ismail, S.; Amr, K.; Aslanger, A.D.; Becker, C.; Netzer, C.; Scambler, P.; Eyaid, W.; Hamamy, H.; Clayton-Smith, J.; Hennekam, R.; Nurnberg, P.; Herz, J.; Temtamy, S.A.; Wollnik, B. Lrp4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome. Am. J. Hum. Genet. , 86, 696–706.
[36]
Schneider, W.J.; Nimpf, J. LDL receptor relatives at the crossroad of endocytosis and signaling. Cell Mol. Life Sci. 2003, 60, 892–903.
[37]
Niehrs, C.; Shen, J. Regulation of Lrp6 phosphorylation. Cell Mol. Life Sci. 2010, 67, 2551–2562.
[38]
Gao, C.; Chen, Y.G. Dishevelled: The hub of Wnt signaling. Cell. Signal 2010, 22, 717–727.
Yamamoto, H.; Komekado, H.; Kikuchi, A. Caveolin is necessary for Wnt-3a-dependent internalization of LRP6 and accumulation of beta-catenin. Dev. Cell 2006, 11, 213–223.
[45]
Yamamoto, S.; Nishimura, O.; Misaki, K.; Nishita, M.; Minami, Y.; Yonemura, S.; Tarui, H.; Sasaki, H. Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex. Dev. Cell 2008, 15, 23–36.
[46]
Ahn, Y.; Sanderson, B.W.; Klein, O.D.; Krumlauf, R. Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning. Development 2010, 137, 3221–3231.
[47]
Clausen, K.A.; Blish, K.R.; Birse, C.E.; Triplette, M.A.; Kute, T.E.; Russell, G.B.; D'Agostino, R.B., Jr.; Miller, L.D.; Torti, F.M.; Torti, S.V. SOSTDC1 differentially modulates Smad and beta-catenin activation and is down-regulated in breast cancer. Breast Cancer Res. Treat. 2010, doi:10.1007/s10549-010-1261-9..
[48]
Ellies, D.L.; Viviano, B.; McCarthy, J.; Rey, J.P.; Itasaki, N.; Saunders, S.; Krumlauf, R. Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J. Bone Miner Res. 2006, 21, 1738–1749.
[49]
Kawano, Y.; Kypta, R. Secreted antagonists of the Wnt signalling pathway. J. Cell Sci. 2003, 116, 2627–2634.
[50]
Li, X.; Zhang, Y.; Kang, H.; Liu, W.; Liu, P.; Zhang, J.; Harris, S.E.; Wu, D. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 2005, 280, 19883–19887.
[51]
Mason, J.J.; Williams, B.O. SOST and DKK: Antagonists of LRP family signaling as targets for treating bone disease. J. Osteoporos. 2010, doi:10.4061/2010/460120..
[52]
Niehrs, C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 2006, 25, 7469–7481.
[53]
Semenov, M.; Tamai, K.; He, X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J. Biol. Chem. 2005, 280, 26770–26775.
[54]
Zeng, X.; Huang, H.; Tamai, K.; Zhang, X.; Harada, Y.; Yokota, C.; Almeida, K.; Wang, J.; Doble, B.; Woodgett, J.; Wynshaw-Boris, A.; Hsieh, J.C.; He, X. Initiation of Wnt signaling: Control of Wnt coreceptor LRP6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development 2008, 135, 367–375.
[55]
Bilic, J.; Huang, Y.L.; Davidson, G.; Zimmermann, T.; Cruciat, C.M.; Bienz, M.; Niehrs, C. Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science 2007, 316, 1619–1622.
[56]
MacDonald, B.T.; Yokota, C.; Tamai, K.; Zeng, X.; He, X. Wnt signal amplification via activity, cooperativity, and regulation of multiple intracellular PPPSP motifs in the Wnt co-receptor LRP6. J. Biol. Chem. 2008, 283, 16115–16123.
[57]
Liu, C.; Li, Y.; Semenov, M.; Han, C.; Baeg, G.H.; Tan, Y.; Zhang, Z.; Lin, X.; He, X. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 2002, 108, 837–847.
[58]
Aberle, H.; Bauer, A.; Stappert, J.; Kispert, A.; Kemler, R. Beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997, 16, 3797–3804.
[59]
Wu, X.; Tu, X.; Joeng, K.S.; Hilton, M.J.; Williams, D.A.; Long, F. Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling. Cell 2008, 133, 340–353.
[60]
Phelps, R.A.; Chidester, S.; Dehghanizadeh, S.; Phelps, J.; Sandoval, I.T.; Rai, K.; Broadbent, T.; Sarkar, S.; Burt, R.W.; Jones, D.A. A two-step model for colon adenoma initiation and progression caused by APC loss. Cell 2009, 137, 623–634.
[61]
Clevers, H.; van de Wetering, M. Tcf/lef factor earn their wings. Trends Genet. 1997, 13, 485–489.
Diegel, C.R.; Cho, K.R.; El-Naggar, A.K.; Williams, B.O.; Lindvall, C. Mammalian target of rapamycin-dependent acinar cell neoplasia after inactivation of Apc and Pten in the mouse salivary gland: Implications for human acinic cell carcinoma. Cancer Res. 2010, 70, 9143–9152.
[66]
Veeman, M.T.; Axelrod, J.D.; Moon, R.T. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev. Cell 2003, 5, 367–377.
[67]
Grumolato, L.; Liu, G.; Mong, P.; Mudbhary, R.; Biswas, R.; Arroyave, R.; Vijayakumar, S.; Economides, A.N.; Aaronson, S.A. Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors. Genes Dev. 2010, 24, 2517–2530.
[68]
Lee, J.M.; Kim, I.S.; Kim, H.; Lee, J.S.; Kim, K.; Yim, H.Y.; Jeong, J.; Kim, J.H.; Kim, J.Y.; Lee, H.; Seo, S.B.; Rosenfeld, M.G.; Kim, K.I.; Baek, S.H. RORalpha attenuates Wnt/beta-catenin signaling by PKCalpha-dependent phosphorylation in colon cancer. Mol. Cell 2010, 37, 183–195.
[69]
Lyu, J.; Yamamoto, V.; Lu, W. Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis. Dev. Cell 2008, 15, 773–780.
[70]
Pinto, D.; Clevers, H. Wnt, stem cells and cancer in the intestine. Biol. Cell 2005, 97, 185–196.
[71]
Scoville, D.H.; Sato, T.; He, X.C.; Li, L. Current view: Intestinal stem cells and signaling. Gastroenterology 2008, 134, 849–864.
[72]
Potten, C.S. Extreme sensitivity of some intestinal crypt cells to X and gamma irradiation. Nature 1977, 269, 518–521.
[73]
Potten, C.S.; Kovacs, L.; Hamilton, E. Continuous labelling studies on mouse skin and intestine. Cell Tissue Kinet. 1974, 7, 271–283.
[74]
Korinek, V.; Barker, N.; Moerer, P.; van Donselaar, E.; Huls, G.; Peters, P.J.; Clevers, H. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat. Genet. 1998, 19, 379–383.
[75]
Fevr, T.; Robine, S.; Louvard, D.; Huelsken, J. Wnt/beta-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol. Cell Biol. 2007, 27, 7551–7559.
[76]
Pinto, D.; Gregorieff, A.; Begthel, H.; Clevers, H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 2003, 17, 1709–1713.
[77]
Kuhnert, F.; Davis, C.R.; Wang, H.T.; Chu, P.; Lee, M.; Yuan, J.; Nusse, R.; Kuo, C.J. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc. Natl. Acad. Sci. USA. 2004, 101, 266–271.
[78]
Rezza, A.; Skah, S.; Roche, C.; Nadjar, J.; Samarut, J.; Plateroti, M. The overexpression of the putative gut stem cell marker Musashi-1 induces tumorigenesis through Wnt and Notch activation. J. Cell Sci. 2010, 123, 3256–3265.
[79]
Barker, N.; van Es, J.H.; Kuipers, J.; Kujala, P.; van den Born, M.; Cozijnsen, M.; Haegebarth, A.; Korving, J.; Begthel, H.; Peters, P.J.; Clevers, H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007, 449, 1003–1007.
[80]
Hou, N.Y.; Yang, K.; Chen, T.; Chen, X.Z.; Zhang, B.; Mo, X.M.; Hu, J.K. CD133(+)CD44 (+) subgroups may be human small intestinal stem cells. Mol. Biol. Rep. 2010, 38, 997–1004.
[81]
Snippert, H.J.; van der Flier, L.G.; Sato, T.; van Es, J.H.; van den Born, M.; Kroon-Veenboer, C.; Barker, N.; Klein, A.M.; van Rheenen, J.; Simons, B.D.; Clevers, H. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 2010, 143, 134–144.
[82]
Sato, T.; Vries, R.G.; Snippert, H.J.; van de Wetering, M.; Barker, N.; Stange, D.E.; van Es, J.H.; Abo, A.; Kujala, P.; Peters, P.J.; Clevers, H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 2009, 459, 262–265.
[83]
Holcombe, R.F.; Marsh, J.L.; Waterman, M.L.; Lin, F.; Milovanovic, T.; Truong, T. Expression of Wnt ligands and Frizzled receptors in colonic mucosa and in colon carcinoma. Mol. Pathol. 2002, 55, 220–226.
[84]
Liu, W.; Dong, X.; Mai, M.; Seelan, R.S.; Taniguchi, K.; Krishnadath, K.K.; Halling, K.C.; Cunningham, J.M.; Boardman, L.A.; Qian, C.; Christensen, E.; Schmidt, S.S.; Roche, P.C.; Smith, D.I.; Thibodeau, S.N. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. Nat. Genet. 2000, 26, 146–147.
[85]
Polakis, P. Wnt signaling and cancer. Genes Dev. 2000, 14, 1837–1851.
[86]
Nishisho, I.; Nakamura, Y.; Miyoshi, Y.; Miki, Y.; Ando, H.; Horii, A.; Koyama, K.; Utsunomiya, J.; Baba, S.; Hedge, P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991, 253, 665–669.
[87]
Moser, A.R.; Pitot, H.C.; Dove, W.F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 1990, 247, 322–324.
[88]
Petersen, G.M.; Brensinger, J.D.; Johnson, K.A.; Giardiello, F.M. Genetic testing and counseling for hereditary forms of colorectal cancer. Cancer 1999, 86, 2540–2550.
[89]
Sparks, A.B.; Morin, P.J.; Vogelstein, B.; Kinzler, K.W. Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res. 1998, 58, 1130–1134.
[90]
Aoki, K.; Tamai, Y.; Horiike, S.; Oshima, M.; Taketo, M.M. Colonic polyposis caused by mtor-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice. Nat. Genet. 2003, 35, 323–330.
[91]
Fodde, R.; Edelmann, W.; Yang, K.; van Leeuwen, C.; Carlson, C.; Renault, B.; Breukel, C.; Alt, E.; Lipkin, M.; Khan, P.M.; et al. A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc. Natl. Acad. Sci. USA 1994, 91, 8969–8973.
[92]
Oshima, M.; Oshima, H.; Kitagawa, K.; Kobayashi, M.; Itakura, C.; Taketo, M. Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proc. Natl. Acad. Sci. USA 1995, 92, 4482–4486.
[93]
Su, L.K.; Kinzler, K.W.; Vogelstein, B.; Preisinger, A.C.; Moser, A.R.; Luongo, C.; Gould, K.A.; Dove, W.F. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 1992, 256, 668–670.
[94]
Moser, A.R.; Dove, W.F.; Roth, K.A.; Gordon, J.I. The Min (multiple intestinal neoplasia) mutation: Its effect on gut epithelial cell differentiation and interaction with a modifier system. J. Cell Biol. 1992, 116, 1517–1526.
[95]
Barker, N.; Ridgway, R.A.; van Es, J.H.; van de Wetering, M.; Begthel, H.; van den Born, M.; Danenberg, E.; Clarke, A.R.; Sansom, O.J.; Clevers, H. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 2009, 457, 608–611.
[96]
Lewis, A.; Segditsas, S.; Deheragoda, M.; Pollard, P.; Jeffery, R.; Nye, E.; Lockstone, H.; Davis, H.; Stamp, G.; Poulsom, R.; Wright, N.; Tomlinson, I. Severe polyposis in Apc1322T mice is associated with submaximal Wnt signalling and increased expression of the stem cell marker Lgr5. Gut. 2010, 59, 1680–1686.
[97]
Zeilstra, J.; Joosten, S.P.; Dokter, M.; Verwiel, E.; Spaargaren, M.; Pals, S.T. Deletion of the Wnt target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res. 2008, 68, 3655–3661.
[98]
Dalerba, P.; Dylla, S.J.; Park, I.K.; Liu, R.; Wang, X.; Cho, R.W.; Hoey, T.; Gurney, A.; Huang, E.H.; Simeone, D.M.; Shelton, A.A.; Parmiani, G.; Castelli, C.; Clarke, M.F. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA 2007, 104, 10158–10163.
[99]
Tetsu, O.; McCormick, F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999, 398, 422–426.
[100]
van de Wetering, M.; Sancho, E.; Verweij, C.; de Lau, W.; Oving, I.; Hurlstone, A.; van der Horn, K.; Batlle, E.; Coudreuse, D.; Haramis, A.P.; Tjon-Pon-Fong, M.; Moerer, P.; van den Born, M.; Soete, G.; Pals, S.; Eilers, M.; Medema, R.; Clevers, H. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002, 111, 241–250.
[101]
Suzuki, H.; Watkins, D.N.; Jair, K.W.; Schuebel, K.E.; Markowitz, S.D.; Chen, W.D.; Pretlow, T.P.; Yang, B.; Akiyama, Y.; Van Engeland, M.; Toyota, M.; Tokino, T.; Hinoda, Y.; Imai, K.; Herman, J.G.; Baylin, S.B. Epigenetic inactivation of SFRP genes allows constitutive Wnt signaling in colorectal cancer. Nat. Genet. 2004, 36, 417–422.
[102]
Jiang, X.; Tan, J.; Li, J.; Kivimae, S.; Yang, X.; Zhuang, L.; Lee, P.L.; Chan, M.T.; Stanton, L.W.; Liu, E.T.; Cheyette, B.N.; Yu, Q. DACT3 is an epigenetic regulator of Wnt/beta-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell 2008, 13, 529–541.
[103]
Shackleton, M.; Vaillant, F.; Simpson, K.J.; Stingl, J.; Smyth, G.K.; Asselin-Labat, M.L.; Wu, L.; Lindeman, G.J.; Visvader, J.E. Generation of a functional mammary gland from a single stem cell. Nature 2006, 439, 84–88.
[104]
Sleeman, K.E.; Kendrick, H.; Ashworth, A.; Isacke, C.M.; Smalley, M.J. CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast Cancer Res. 2006, 8, R7.
[105]
Stingl, J.; Eirew, P.; Ricketson, I.; Shackleton, M.; Vaillant, F.; Choi, D.; Li, H.I.; Eaves, C.J. Purification and unique properties of mammary epithelial stem cells. Nature 2006, 439, 993–997.
[106]
Eirew, P.; Stingl, J.; Raouf, A.; Turashvili, G.; Aparicio, S.; Emerman, J.T.; Eaves, C.J. A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability. Nat. Med. 2008, 14, 1384–1389.
[107]
Lim, E.; Vaillant, F.; Wu, D.; Forrest, N.C.; Pal, B.; Hart, A.H.; Asselin-Labat, M.L.; Gyorki, D.E.; Ward, T.; Partanen, A.; Feleppa, F.; Huschtscha, L.I.; Thorne, H.J.; Fox, S.B.; Yan, M.; French, J.D.; Brown, M.A.; Smyth, G.K.; Visvader, J.E.; Lindeman, G.J. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat. Med. 2009, 15, 907–913.
[108]
Chu, E.Y.; Hens, J.; Andl, T.; Kairo, A.; Yamaguchi, T.P.; Brisken, C.; Glick, A.; Wysolmerski, J.J.; Millar, S.E. Canonical Wnt signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development 2004, 131, 4819–4829.
[109]
Veltmaat, J.M.; Mailleux, A.A.; Thiery, J.P.; Bellusci, S. Mouse embryonic mammogenesis as a model for the molecular regulation of pattern formation. Differentiation 2003, 71, 1–17.
[110]
Lindvall, C.; Zylstra, C.R.; Evans, N.; West, R.A.; Dykema, K.; Furge, K.A.; Williams, B.O. The Wnt co-receptor Lrp6 is required for normal mouse mammary gland development. PLoS One 2009, 4, e5813.
[111]
Andl, T.; Reddy, S.T.; Gaddapara, T.; Millar, S.E. Wnt signals are required for the initiation of hair follicle development. Dev. Cell 2002, 2, 643–653.
[112]
van Genderen, C.; Okamura, R.M.; Farinas, I.; Quo, R.G.; Parslow, T.G.; Bruhn, L.; Grosschedl, R. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev. 1994, 8, 2691–2703.
[113]
Kouros-Mehr, H.; Werb, Z. Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev. Dyn. 2006, 235, 3404–3412.
[114]
Lindvall, C.; Evans, N.C.; Zylstra, C.R.; Li, Y.; Alexander, C.M.; Williams, B.O. The Wnt signaling receptor Lrp5 is required for mammary ductal stem cell activity and Wnt1-induced tumorigenesis. J. Biol. Chem. 2006, 281, 35081–35087.
[115]
Roarty, K.; Serra, R. Wnt5a is required for proper mammary gland development and TGF-beta-mediated inhibition of ductal growth. Development 2007, 134, 3929–3939.
[116]
Bradbury, J.M.; Edwards, P.A.; Niemeyer, C.C.; Dale, T.C. Wnt-4 expression induces a pregnancy-like growth pattern in reconstituted mammary glands in virgin mice. Dev. Biol. 1995, 170, 553–563.
Zeng, Y.A.; Nusse, R. Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell 2010, 6, 568–577.
[121]
Tsukamoto, A.S.; Grosschedl, R.; Guzman, R.C.; Parslow, T.; Varmus, H.E. Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 1988, 55, 619–625.
Teissedre, B.; Pinderhughes, A.; Incassati, A.; Hatsell, S.J.; Hiremath, M.; Cowin, P. MMTV-Wnt1 and -DeltaN89beta-catenin induce canonical signaling in distinct progenitors and differentially activate Hedgehog signaling within mammary tumors. PLoS One 2009, 4, e4537.
[124]
Vaillant, F.; Asselin-Labat, M.L.; Shackleton, M.; Forrest, N.C.; Lindeman, G.J.; Visvader, J.E. The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis. Cancer Res. 2008, 68, 7711–7717.
[125]
Nakopoulou, L.; Gakiopoulou-Givalou, H.; Karayiannakis, A.J.; Giannopoulou, I.; Keramopoulos, A.; Davaris, P.; Pignatelli, M. Abnormal alpha-catenin expression in invasive breast cancer correlates with poor patient survival. Histopathology 2002, 40, 536–546.
[126]
Zardawi, S.J.; O'Toole, S.A.; Sutherland, R.L.; Musgrove, E.A. Dysregulation of Hedgehog, Wnt and Notch signalling pathways in breast cancer. Histol. Histopathol 2009, 24, 385–398.
[127]
Ryo, A.; Nakamura, M.; Wulf, G.; Liou, Y.C.; Lu, K.P. Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC. Nat. Cell Biol. 2001, 3, 793–801.
[128]
Lin, S.Y.; Xia, W.; Wang, J.C.; Kwong, K.Y.; Spohn, B.; Wen, Y.; Pestell, R.G.; Hung, M.C. Beta-catenin, a novel prognostic marker for breast cancer: Its roles in cyclin D1 expression and cancer progression. Proc. Natl. Acad. Sci. USA 2000, 97, 4262–4266.
[129]
Dolled-Filhart, M.; McCabe, A.; Giltnane, J.; Cregger, M.; Camp, R.L.; Rimm, D.L. Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome. Cancer Res. 2006, 66, 5487–5494.
[130]
Karayiannakis, A.J.; Nakopoulou, L.; Gakiopoulou, H.; Keramopoulos, A.; Davaris, P.S.; Pignatelli, M. Expression patterns of beta-catenin in in situ and invasive breast cancer. Eur. J. Surg. Oncol. 2001, 27, 31–36.
[131]
Bukholm, I.K.; Nesland, J.M.; Karesen, R.; Jacobsen, U.; Borresen-Dale, A.L. E-cadherin and alpha-, beta-, and gamma-catenin protein expression in relation to metastasis in human breast carcinoma. J. Pathol. 1998, 185, 262–266.
[132]
Dillon, D.A.; D'Aquila, T.; Reynolds, A.B.; Fearon, E.R.; Rimm, D.L. The expression of p120ctn protein in breast cancer is independent of alpha- and beta-catenin and e-cadherin. Am. J. Pathol. 1998, 152, 75–82.
[133]
Wong, S.C.; Lo, S.F.; Lee, K.C.; Yam, J.W.; Chan, J.K.; Wendy Hsiao, W.L. Expression of frizzled-related protein and Wnt-signalling molecules in invasive human breast tumours. J. Pathol. 2002, 196, 145–153.
[134]
Khramtsov, A.I.; Khramtsova, G.F.; Tretiakova, M.; Huo, D.; Olopade, O.I.; Goss, K.H. Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am. J. Pathol. 2010, 176, 2911–2920.
[135]
Ugolini, F.; Charafe-Jauffret, E.; Bardou, V.J.; Geneix, J.; Adelaide, J.; Labat-Moleur, F.; Penault-Llorca, F.; Longy, M.; Jacquemier, J.; Birnbaum, D.; Pebusque, M.J. Wnt pathway and mammary carcinogenesis: Loss of expression of candidate tumor suppressor gene SFRP1 in most invasive carcinomas except of the medullary type. Oncogene 2001, 20, 5810–5817.
[136]
Veeck, J.; Geisler, C.; Noetzel, E.; Alkaya, S.; Hartmann, A.; Knuchel, R.; Dahl, E. Epigenetic inactivation of the secreted frizzled-related protein-5 (SFRP5) gene in human breast cancer is associated with unfavorable prognosis. Carcinogenesis 2008, 29, 991–998.
[137]
Suzuki, H.; Toyota, M.; Carraway, H.; Gabrielson, E.; Ohmura, T.; Fujikane, T.; Nishikawa, N.; Sogabe, Y.; Nojima, M.; Sonoda, T.; Mori, M.; Hirata, K.; Imai, K.; Shinomura, Y.; Baylin, S.B.; Tokino, T. Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer. Br. J. Cancer 2008, 98, 1147–1156.
[138]
Geyer, F.C.; Lacroix-Triki, M.; Savage, K.; Arnedos, M.; Lambros, M.B.; Mackay, A.; Natrajan, R.; Reis-Filho, J.S. Beta-catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Mod. Pathol. 2010, 24, 209–231.
[139]
Furuuchi, K.; Tada, M.; Yamada, H.; Kataoka, A.; Furuuchi, N.; Hamada, J.; Takahashi, M.; Todo, S.; Moriuchi, T. Somatic mutations of the APC gene in primary breast cancers. Am. J. Pathol. 2000, 156, 1997–2005.
[140]
Woodward, W.A.; Chen, M.S.; Behbod, F.; Alfaro, M.P.; Buchholz, T.A.; Rosen, J.M. Wnt/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc. Natl. Acad. Sci. USA 2007, 104, 618–623.
[141]
Debeb, B.G.; Xu, W.; Woodward, W.A. Radiation resistance of breast cancer stem cells: Understanding the clinical framework. J. Mammary Gland Biol. Neoplasia 2009, 14, 11–17.
[142]
Chen, M.S.; Woodward, W.A.; Behbod, F.; Peddibhotla, S.; Alfaro, M.P.; Buchholz, T.A.; Rosen, J.M. Wnt/beta-catenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line. J. Cell Sci. 2007, 120, 468–477.
[143]
Zhang, M.; Atkinson, R.L.; Rosen, J.M. Selective targeting of radiation-resistant tumor-initiating cells. Proc. Natl. Acad. Sci. USA 2010, 107, 3522–3527.
Garraway, I.P.; Sun, W.; Tran, C.P.; Perner, S.; Zhang, B.; Goldstein, A.S.; Hahm, S.A.; Haider, M.; Head, C.S.; Reiter, R.E.; Rubin, M.A.; Witte, O.N. Human prostate sphere-forming cells represent a subset of basal epithelial cells capable of glandular regeneration in vivo. Prostate 2010, 70, 491–501.
[146]
Lawson, D.A.; Xin, L.; Lukacs, R.U.; Cheng, D.; Witte, O.N. Isolation and functional characterization of murine prostate stem cells. Proc. Natl. Acad. Sci. USA 2007, 104, 181–186.
[147]
Moscatelli, D.; Wilson, E.L. PINing down the origin of prostate cancer. Sci. Transl. Med. , 2, 43ps38.
[148]
Wang, X.; Kruithof-de Julio, M.; Economides, K.D.; Walker, D.; Yu, H.; Halili, M.V.; Hu, Y.P.; Price, S.M.; Abate-Shen, C.; Shen, M.M. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 2009, 461, 495–500.
[149]
Kellokumpu-Lehtinen, P.; Santti, R.; Pelliniemi, L.J. Correlation of early cytodifferentiation of the human fetal prostate and Leydig cells. Anat. Rec. 1980, 196, 263–273.
[150]
Wang, Y.; Hayward, S.; Cao, M.; Thayer, K.; Cunha, G. Cell differentiation lineage in the prostate. Differentiation 2001, 68, 270–279.
[151]
Cleutjens, K.B.; van Eekelen, C.C.; van der Korput, H.A.; Brinkmann, A.O.; Trapman, J. Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter. J. Biol. Chem. 1996, 271, 6379–6388.
Lin, B.; Ferguson, C.; White, J.T.; Wang, S.; Vessella, R.; True, L.D.; Hood, L.; Nelson, P.S. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res. 1999, 59, 4180–4184.
[154]
Cunha, G.R.; Lung, B. The possible influence of temporal factors in androgenic responsiveness of urogenital tissue recombinants from wild-type and androgen-insensitive (Tfm) mice. J. Exp. Zool. 1978, 205, 181–193.
[155]
Furuya, Y.; Isaacs, J.T. Differential gene regulation during programmed death (apoptosis) versus proliferation of prostatic glandular cells induced by androgen manipulation. Endocrinology 1993, 133, 2660–2666.
Zhang, T.J.; Hoffman, B.G.; Ruiz de Algara, T.; Helgason, C.D. SAGE reveals expression of Wnt signalling pathway members during mouse prostate development. Gene Expr. Patterns 2006, 6, 310–324.
[158]
Wang, B.E.; Wang, X.D.; Ernst, J.A.; Polakis, P.; Gao, W.Q. Regulation of epithelial branching morphogenesis and cancer cell growth of the prostate by Wnt signaling. PLoS One 2008, 3, e2186.
Huang, L.; Pu, Y.; Hu, W.Y.; Birch, L.; Luccio-Camelo, D.; Yamaguchi, T.; Prins, G.S. The role of Wnt5a in prostate gland development. Dev. Biol. 2009, 328, 188–199.
[161]
Verras, M.; Sun, Z. Roles and regulation of Wnt signaling and beta-catenin in prostate cancer. Cancer Lett. 2006, 237, 22–32.
[162]
Yardy, G.W.; Brewster, S.F. Wnt signalling and prostate cancer. Prostate Cancer Prostatic Dis. 2005, 8, 119–126.
[163]
Robinson, D.R.; Zylstra, C.R.; Williams, B.O. Wnt signaling and prostate cancer. Curr. Drug Targets 2008, 9, 571–580.
[164]
Marker, P.C. Does prostate cancer co-opt the developmental program? Differentiation 2008, 76, 736–744.
[165]
Hall, C.L.; Bafico, A.; Dai, J.; Aaronson, S.A.; Keller, E.T. Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res. 2005, 65, 7554–7560.
[166]
Chen, G.; Shukeir, N.; Potti, A.; Sircar, K.; Aprikian, A.; Goltzman, D.; Rabbani, S.A. Up-regulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: Potential pathogenetic and prognostic implications. Cancer 2004, 101, 1345–1356.
[167]
Li, Z.G.; Yang, J.; Vazquez, E.S.; Rose, D.; Vakar-Lopez, F.; Mathew, P.; Lopez, A.; Logothetis, C.J.; Lin, S.H.; Navone, N.M. Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone. Oncogene 2008, 27, 596–603.
[168]
Uysal-Onganer, P.; Kawano, Y.; Caro, M.; Walker, M.M.; Diez, S.; Darrington, R.S.; Waxman, J.; Kypta, R.M. Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells. Mol. Cancer 2010, 9, 55.
[169]
Yamamoto, H.; Oue, N.; Sato, A.; Hasegawa, Y.; Matsubara, A.; Yasui, W.; Kikuchi, A. Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase. Oncogene 2010, 29, 2036–2046.
[170]
Hall, C.L.; Daignault, S.D.; Shah, R.B.; Pienta, K.J.; Keller, E.T. Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis. Prostate 2008, 68, 1396–1404.
[171]
Gupta, S.; Iljin, K.; Sara, H.; Mpindi, J.P.; Mirtti, T.; Vainio, P.; Rantala, J.; Alanen, K.; Nees, M.; Kallioniemi, O. FZD4 as a mediator of ERG oncogene-induced Wnt signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 2010, 70, 6735–6745.
[172]
Wissmann, C.; Wild, P.J.; Kaiser, S.; Roepcke, S.; Stoehr, R.; Woenckhaus, M.; Kristiansen, G.; Hsieh, J.C.; Hofstaedter, F.; Hartmann, A.; Knuechel, R.; Rosenthal, A.; Pilarsky, C. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. J. Pathol. 2003, 201, 204–212.
[173]
Yee, D.S.; Tang, Y.; Li, X.; Liu, Z.; Guo, Y.; Ghaffar, S.; McQueen, P.; Atreya, D.; Xie, J.; Simoneau, A.R.; Hoang, B.H.; Zi, X. The Wnt inhibitory factor 1 restoration in prostate cancer cells was associated with reduced tumor growth, decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition. Mol. Cancer 2010, 9, 162.
[174]
Ohigashi, T.; Mizuno, R.; Nakashima, J.; Marumo, K.; Murai, M. Inhibition of Wnt signaling downregulates Akt activity and induces chemosensitivity in PTEN-mutated prostate cancer cells. Prostate 2005, 62, 61–68.
[175]
Wu, X.; Wu, J.; Huang, J.; Powell, W.C.; Zhang, J.; Matusik, R.J.; Sangiorgi, F.O.; Maxson, R.E.; Sucov, H.M.; Roy-Burman, P. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech. Dev. 2001, 101, 61–69.
[176]
Chesire, D.R.; Ewing, C.M.; Sauvageot, J.; Bova, G.S.; Isaacs, W.B. Detection and analysis of beta-catenin mutations in prostate cancer. Prostate 2000, 45, 323–334.
[177]
Gerstein, A.V.; Almeida, T.A.; Zhao, G.; Chess, E.; Shih Ie, M.; Buhler, K.; Pienta, K.; Rubin, M.A.; Vessella, R.; Papadopoulos, N. APC/CTNNB1 (beta-catenin) pathway alterations in human prostate cancers. Gene. Chromosome. Cancer 2002, 34, 9–16.
[178]
Richiardi, L.; Fiano, V.; Vizzini, L.; De Marco, L.; Delsedime, L.; Akre, O.; Tos, A.G.; Merletti, F. Promoter methylation in APC, RUNX3, and GSTP1 and mortality in prostate cancer patients. J. Clin. Oncol. 2009, 27, 3161–3168.
Pearson, H.B.; Phesse, T.J.; Clarke, A.R. K-ras and Wnt signaling synergize to accelerate prostate tumorigenesis in the mouse. Cancer Res. 2009, 69, 94–101.
[181]
Yu, X.; Wang, Y.; Jiang, M.; Bierie, B.; Roy-Burman, P.; Shen, M.M.; Taketo, M.M.; Wills, M.; Matusik, R.J. Activation of beta-catenin in mouse prostate causes HGPIN and continuous prostate growth after castration. Prostate 2009, 69, 249–262.
[182]
Sarkar, F.H.; Li, Y.; Wang, Z.; Kong, D. Novel targets for prostate cancer chemoprevention. Endocr. Relat. Cancer , 17, R195–212.
[183]
Collins, A.T.; Berry, P.A.; Hyde, C.; Stower, M.J.; Maitland, N.J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005, 65, 10946–10951.
[184]
Goldstein, A.S.; Huang, J.; Guo, C.; Garraway, I.P.; Witte, O.N. Identification of a cell of origin for human prostate cancer. Science 2010, 329, 568–571.
[185]
Leong, K.G.; Wang, B.E.; Johnson, L.; Gao, W.Q. Generation of a prostate from a single adult stem cell. Nature 2008, 456, 804–808.
[186]
Maitland, N.J.; Bryce, S.D.; Stower, M.J.; Collins, A.T. Prostate cancer stem cells: A target for new therapies. Ernst Schering Found Symp. Proc. 2006, 155–179.
[187]
Bisson, I.; Prowse, D.M. Wnt signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res. 2009, 19, 683–697.
[188]
Zhu, H.; Mazor, M.; Kawano, Y.; Walker, M.M.; Leung, H.Y.; Armstrong, K.; Waxman, J.; Kypta, R.M. Analysis of Wnt gene expression in prostate cancer: Mutual inhibition by Wnt11 and the androgen receptor. Cancer Res. 2004, 64, 7918–7926.
[189]
Verras, M.; Brown, J.; Li, X.; Nusse, R.; Sun, Z. Wnt3a growth factor induces androgen receptor-mediated transcription and enhances cell growth in human prostate cancer cells. Cancer Res. 2004, 64, 8860–8866.
[190]
Chesire, D.R.; Ewing, C.M.; Gage, W.R.; Isaacs, W.B. In vitro evidence for complex modes of nuclear beta-catenin signaling during prostate growth and tumorigenesis. Oncogene 2002, 21, 2679–2694.
[191]
Wend, P.; Holland, J.D.; Ziebold, U.; Birchmeier, W. Wnt signaling in stem and cancer stem cells. Semin. Cell Dev. Biol. 2010, 21, 855–863.
[192]
Polakis, P. The many ways of Wnt in cancer. Curr. Opin. Genet. Dev. 2007, 17, 45–51.
[193]
Barker, N.; Clevers, H. Mining the Wnt pathway for cancer therapeutics. Nat. Rev. Drug Discov. 2006, 5, 997–1014.
[194]
Reya, T.; Morrison, S.J.; Clarke, M.F.; Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 2001, 414, 105–111.
[195]
Castellone, M.D.; Teramoto, H.; Williams, B.O.; Druey, K.M.; Gutkind, J.S. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 2005, 310, 1504–1510.
[196]
Labayle, D.; Fischer, D.; Vielh, P.; Drouhin, F.; Pariente, A.; Bories, C.; Duhamel, O.; Trousset, M.; Attali, P. Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 1991, 101, 635–639.
[197]
Boon, E.M.; Keller, J.J.; Wormhoudt, T.A.; Giardiello, F.M.; Offerhaus, G.J.; van der Neut, R.; Pals, S.T. Sulindac targets nuclear beta-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines. Br. J. Cancer 2004, 90, 224–229.
[198]
Dihlmann, S.; Siermann, A.; von Knebel Doeberitz, M. The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate beta-catenin/TCF-4 signaling. Oncogene 2001, 20, 645–653.
[199]
Akhter, J.; Chen, X.; Bowrey, P.; Bolton, E.J.; Morris, D.L. Vitamin D3 analog, EB1089, inhibits growth of subcutaneous xenografts of the human colon cancer cell line, LoVo, in a nude mouse model. Dis. Colon Rectum. 1997, 40, 317–321.
[200]
Harris, D.M.; Go, V.L. Vitamin D and colon carcinogenesis. J. Nutr. 2004, 134, 3463S–3471S.
[201]
VanWeelden, K.; Flanagan, L.; Binderup, L.; Tenniswood, M.; Welsh, J. Apoptotic regression of MCF-7 xenografts in nude mice treated with the vitamin D3 analog, EB1089. Endocrinology 1998, 139, 2102–2110.
[202]
Palmer, H.G.; Gonzalez-Sancho, J.M.; Espada, J.; Berciano, M.T.; Puig, I.; Baulida, J.; Quintanilla, M.; Cano, A.; de Herreros, A.G.; Lafarga, M.; Munoz, A. Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J. Cell Biol. 2001, 154, 369–387.
[203]
Shah, S.; Islam, M.N.; Dakshanamurthy, S.; Rizvi, I.; Rao, M.; Herrell, R.; Zinser, G.; Valrance, M.; Aranda, A.; Moras, D.; Norman, A.; Welsh, J.; Byers, S.W. The molecular basis of vitamin D receptor and beta-catenin crossregulation. Mol. Cell 2006, 21, 799–809.
[204]
Sarkar, F.H.; Li, Y.; Wang, Z.; Kong, D. The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer. Cancer Metastasis Rev. 2010, 29, 383–394.
[205]
Itasaki, N.; Jones, C.M.; Mercurio, S.; Rowe, A.; Domingos, P.M.; Smith, J.C.; Krumlauf, R. Wise, a context-dependent activator and inhibitor of Wnt signalling. Development 2003, 130, 4295–4305.
[206]
Lu, W.; Liu, C.C.; Thottassery, J.V.; Bu, G.; Li, Y. Mesd is a universal inhibitor of wnt coreceptors LRP5 and LRP6 and blocks Wnt/beta-catenin signaling in cancer cells. Biochemistry 2010, 49, 4635–4643.
[207]
Ettenberg, S.A.; Charlat, O.; Daley, M.P.; Liu, S.; Vincent, K.J.; Stuart, D.D.; Schuller, A.G.; Yuan, J.; Ospina, B.; Green, J.; Yu, Q.; Walsh, R.; Li, S.; Schmitz, R.; Heine, H.; Bilic, S.; Ostrom, L.; Mosher, R.; Hartlepp, K.F.; Zhu, Z.; Fawell, S.; Yao, Y.M.; Stover, D.; Finan, P.M.; Porter, J.A.; Sellers, W.R.; Klagge, I.M.; Cong, F. Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies. Proc. Natl. Acad. Sci. USA 2010, 107, 15473–15478.
[208]
Gong, Y.; Bourhis, E.; Chiu, C.; Stawicki, S.; DeAlmeida, V.I.; Liu, B.Y.; Phamluong, K.; Cao, T.C.; Carano, R.A.; Ernst, J.A.; Solloway, M.; Rubinfeld, B.; Hannoush, R.N.; Wu, Y.; Polakis, P.; Costa, M. Wnt isoform-specific interactions with coreceptor specify inhibition or potentiation of signaling by LRP6 antibodies. PLoS One 2010, 5, e12682.
[209]
He, B.; You, L.; Uematsu, K.; Xu, Z.; Lee, A.Y.; Matsangou, M.; McCormick, F.; Jablons, D.M. A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells. Neoplasia 2004, 6, 7–14.
[210]
Mazieres, J.; You, L.; He, B.; Xu, Z.; Twogood, S.; Lee, A.Y.; Reguart, N.; Batra, S.; Mikami, I.; Jablons, D.M. Wnt2 as a new therapeutic target in malignant pleural mesothelioma. Int. J. Cancer 2005, 117, 326–332.
[211]
You, L.; He, B.; Xu, Z.; Uematsu, K.; Mazieres, J.; Fujii, N.; Mikami, I.; Reguart, N.; McIntosh, J.K.; Kashani-Sabet, M.; McCormick, F.; Jablons, D.M. An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth. Cancer Res. 2004, 64, 5385–5389.
[212]
You, L.; He, B.; Xu, Z.; Uematsu, K.; Mazieres, J.; Mikami, I.; Reguart, N.; Moody, T.W.; Kitajewski, J.; McCormick, F.; Jablons, D.M. Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells. Oncogene 2004, 23, 6170–6174.
[213]
You, L.; Kim, J.; He, B.; Xu, Z.; McCormick, F.; Jablons, D.M. Wnt-1 signal as a potential cancer therapeutic target. Drug News Perspect. 2006, 19, 27–31.
[214]
Rhee, C.S.; Sen, M.; Lu, D.; Wu, C.; Leoni, L.; Rubin, J.; Corr, M.; Carson, D.A. Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas. Oncogene 2002, 21, 6598–6605.
[215]
Lepourcelet, M.; Chen, Y.N.; France, D.S.; Wang, H.; Crews, P.; Petersen, F.; Bruseo, C.; Wood, A.W.; Shivdasani, R.A. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 2004, 5, 91–102.
[216]
Emami, K.H.; Nguyen, C.; Ma, H.; Kim, D.H.; Jeong, K.W.; Eguchi, M.; Moon, R.T.; Teo, J.L.; Kim, H.Y.; Moon, S.H.; Ha, J.R.; Kahn, M. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc. Natl. Acad. Sci. USA 2004, 101, 12682–12687.
[217]
Garber, K. Drugging the Wnt pathway: Problems and progress. J. Natl. Cancer Inst. 2009, 101, 548–550.
Chung, N.; Marine, S.; Smith, E.A.; Liehr, R.; Smith, S.T.; Locco, L.; Hudak, E.; Kreamer, A.; Rush, A.; Roberts, B.; Major, M.B.; Moon, R.T.; Arthur, W.; Cleary, M.; Strulovici, B.; Ferrer, M. A 1,536-well ultra-high-throughput sirna screen to identify regulators of the Wnt/beta-catenin pathway. Assay Drug Dev. Technol. 2010, 8, 286–294.
[223]
Sato, N.; Yamabuki, T.; Takano, A.; Koinuma, J.; Aragaki, M.; Masuda, K.; Ishikawa, N.; Kohno, N.; Ito, H.; Miyamoto, M.; Nakayama, H.; Miyagi, Y.; Tsuchiya, E.; Kondo, S.; Nakamura, Y.; Daigo, Y. Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy. Cancer Res. 2010, 70, 5326–5336.
[224]
Holmen, S.L.; Zylstra, C.R.; Mukherjee, A.; Sigler, R.E.; Faugere, M.C.; Bouxsein, M.L.; Deng, L.; Clemens, T.L.; Williams, B.O. Essential role of beta-catenin in postnatal bone acquisition. J. Biol. Chem. 2005, 280, 21162–21168.
[225]
Heiland, G.R.; Zwerina, K.; Baum, W.; Kireva, T.; Distler, J.H.; Grisanti, M.; Asuncion, F.; Li, X.; Ominsky, M.; Richards, W.; Schett, G.; Zwerina, J. Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. Ann. Rheum Dis. 2010, 69, 2152–2159.
[226]
Wang, Y.; Krivtsov, A.V.; Sinha, A.U.; North, T.E.; Goessling, W.; Feng, Z.; Zon, L.I.; Armstrong, S.A. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010, 327, 1650–1653.
[227]
Thompson, M.D.; Monga, S.P. Wnt/beta-catenin signaling in liver health and disease. Hepatology 2007, 45, 1298–1305.
[228]
Rey, J.P.; Ellies, D.L. Wnt modulators in the biotech pipeline. Dev. Dyn. 2010, 239, 102–114.
