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Prostate Cancer and Prostatic Diseases (2005) 8, 119–126 & 2005 Nature Publishing Group All rights reserved 1365-7852/05 $30.00 www.nature.com/pcan Review Wnt signalling and prostate cancer GW Yardy1,2* & SF Brewster2 1Cancer & Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK; and 2Department of Urology, Churchill Hospital, Oxford, UK The Wnt signalling pathway plays a role in the direction of embryological development and maintenance of stem cell populations. Heritable alterations in genes encoding molecules of the Wnt pathway, including mutation and epigenetic events, have been demonstrated in a variety of cancers. It has been proposed that disruption of this pathway is a significant step in the development of many tumours. Interactions between b-catenin—the effector molecule of the Wnt pathway—and the androgen receptor highlight the pathway’s relevance to urological malignancy. Mutation or altered expression of Wnt genes in tumours may give prognostic information and treatments are being developed which target this pathway. Prostate Cancer and Prostatic Diseases (2005) 8, 119–126. doi:10.1038/sj.pcan.4500794 Published online 5 April 2005 Keywords: Wnt signalling; b-catenin Introduction Figure 1 illustrates the interaction of the components of the Wnt signalling pathway. The central molecule of The Wnt pathway directs embryonic growth, governing the pathway is b-catenin, which exists in three cellular processes such as cell fate specification, proliferation, pools10—at the membrane (associated with E-cadherin, polarity and migration. It is also implicated in main- a-catenin and other molecules, involved in cell adhe- tenance of stem cell populations. It is conserved in sion), cytoplasmic and nuclear. In the left-hand part of organisms from worms to mammals and its mechanism diagram, in the absence of a Wnt signal, a multiprotein was first elucidated through analysis of Wingless complex including APC, GSK3b and the scaffold protein signalling, its Drosophila homolog.1 Wnt proteins—a axin phosphorylates free cytoplasmic b-catenin, marking large family of cysteine-rich secreted ligands—bind to it for degradation by ubiquitin.11,12 The kinetics of the a class of seven-pass transmembrane receptors encoded protein–protein interactions of the constituents of this by the frizzled genes2 transducing a signal to the complex have been represented by a mathematical cytoplasmic protein Dishevelled (Dvl),3 which is re- model.13 The presence of a Wnt ligand at the transmem- cruited to the membrane, forms a complex with Axin4 brane receptor Frizzled activates the cytoplasmic protein and induces its dephosphorylation.5 Axin (product of the Dishevelled, which dephosphorylates axin. This de- gene AXIN1) acts as a scaffold protein maintaining the creases the capacity of axin to form complexes with configuration of a complex involving APC (encoded by APC and b-catenin. Conductin, a protein with structural the Adenomatous Polyposis Coli gene6) and b-catenin homology to axin and encoded by the gene AXIN2,14 can (encoded by CTNNB17) and facilitating phosphorylation function in a similar way to axin in this protein of both APC8 and b-catenin9 by glycogen synthase kinase complex.15 Phosphorylation of b-catenin by GSK3b, and 3b (GSK3b). hence degradation of b-catenin by ubiquitin, is de- creased. Cytoplasmic b-catenin thus accumulates and is translocated to the nucleus16 where it associates with *Correspondence: GW Yardy, Cancer & Immunogenetics Laboratory, members of the T-cell factor (TCF) and lymphoid Weatherall Insitute of Molecular Medicine, John Radcliffe Hospital, enhancer factor (LEF) family of transcriptional factors.17 Oxford, UK. The b-catenin–TCF/LEF complex activates transcription E-mail: [email protected] 18 Received 13 November 2004; revised 23 January 2005; accepted 30 of target genes including c-MYC, c-jun and fra-1 January 2005; published online 5 April 2005 (components of the AP-1 transcription complex) and Wnt signalling and prostate cancer GW Yardy and SF Brewster 120 Wnt Frizzled receptor DVL GSK3β n i A t c P actin u n C i d x β n o α GSK3 APC A -cat C n E cadherin i x β -catenin A β-catenin Conductin β-catenin β -catenin β-catenin degradation β-catenin TCF/ LEF β -catenin TCF/ Transcription LEF target genes inc. c-myc, c-jun, fra-1, matrilysin, cyclin D1 Figure 1 The Wnt signalling pathway. DVL—dishevelled, GSK3b—glycogen synthase kinase b, APC—adenomatous polyposis coli, a-cat—a-catenin, TCF/LEF—T-cell factor/lymphoid enhancer factor transcription factors. uPAR (the urokinase-type plasminogen activator recep- Phosphatidylinositol 3-kinase/Akt pathway effector tor),19 the metalloproteinases matrilysin20 and MMP-2621 molecules, through inhibition of GSK3b, control cyto- and cyclin D1.22 plasmic b-catenin levels.29 Siah-1 (the human homolog of Although mainly understood to be active in the Drosophila seven in absentia), a p53-inducible mediator of cytoplasm in the protein complex described above, axin cell cycle arrest, tumour suppression and apoptosis, is also shuttled in and out of the nucleus23 and appears to interacts with APC and promotes degradation of shuttle b-catenin back to the cytoplasm with it,24 further cytoplasmic b-catenin via a mechanism independent of limiting the effects of Wnt pathway activation. GSK3b.30–32 b-catenin binds to and inhibits the activity of Closer analysis of conductin’s function is equally the transcription factor NFkB in breast and colon cancer intriguing. As well as participating in the b-catenin cells.33,34 Ozz-E3, a muscle-specific ubiquitin ligase destruction complex, its gene, AXIN2, is a target of TCF/ adaptor, regulates b-catenin levels at the cell membrane LEF transcription—acting as a negative feedback me- in muscle cells.35 Protein phosphatase 2A also inhibits chanism to control Wnt pathway activation.25,26 the axin/APC/GSK3bb-catenin destruction complex36 In summary, activation of the pathway by the presence and the structural basis for this interaction has been of a Wnt molecule on the cell surface receptor decreases elucidated.37 phosphorylation of b-catenin by the APC/axin/GSK3b Retinoid receptors have an influence. Retinoic acid complex. b-catenin is thus not degraded, and accumu- receptor (RAR) decreases the activity of b-catenin–TCF/ lates in the nucleus, where it stimulates transcription of a LEF transcription independently of the APC pathway.38–40 variety of cancer-associated genes. Retinoid X receptor (RXR) facilitates degradation of b-catenin by another pathway independent of APC.41 Gene transcription by TCF-4 is also under the control of Interactions, Wnt signalling disruption the p53 signalling network42 and a feedback loop between and oncogenesis the actions of deregulated b-catenin, Axin and p53 has been demonstrated, which may be protective against Intracellular signalling pathways are frequently found to oncogenesis.43 Integrin-linked kinase and cyclin-depen- be interconnected; the Wnt pathway is not an exception. dent kinase 2 also influence the Wnt pathway at multiple Some interacting pathways are displayed in Figure 2. points.44–46 The pathway interaction, which may be most Insulin-like growth factor (IGF) type 1 receptor stimula- relevant to prostatic tumorigenesis, is the recently tion facilitates dissociation of b-catenin at the cell observed function of b-catenin as a coactivator of the membrane into the cytoplasmic pool in colorectal cells27 androgen receptor. This will be described in detail below. and potentiates b-catenin–TCF/LEF transcription in Abnormal activation of the pathway, such as muta- hepatoma cells.28 tions that lock the pathway into a ligand-independent Prostate Cancer and Prostatic Diseases Wnt signalling and prostate cancer GW Yardy and SF Brewster 121 Wnt Frizzled receptor PI3K/Akt/PTEN pathway DVL PP2A inhibit IGFs GSK3β n i A t c P actin u n C Siah-1 i d x β n o GSK3 APC activates A α-cat C n E cadherin i x β-catenin A β-catenin Conductin β-catenin RXR degrades β-catenin Ozz-E3 IGFs β -catenin β-catenin degradation β-catenin AR RAR TCF/ LEF β-catenin AR NFκB β-catenin TCF/ Transcription LEF target genes inc. c-myc, c-jun, fra-1, matrilysin, cyclin D1 Figure 2 Some influences of other signalling pathways and factors on the Wnt pathway. PP2A—protein phosphatase 2A, IGFs—insulin-like growth factors, Siah-1—human homolog of Drosophila seven in absentia, AR—androgen receptor, RAR—retinoic acid receptor A, RXR—retinoid X receptor, NFkB—nuclear factor kappa B transcription factor. state of constitutive activation, result in mis-specification mechanisms other that CTNNB1 mutation were also of cells towards stem cell or stem cell-like fates, which activating Wnt signalling abnormally.59 may give rise to neoplasia. Hepatocellular carcinoma (HCC) also showed nuclear APC mutation is a common occurrence in carcinoma of b-catenin more frequently than CTNNB1 mutation. This the colon.47 The gene is somatically altered in at least prompted a search for AXIN1 mutations in six HCC cell 60% of sporadic tumours48 and familial adenomatous lines and 100 primary HCCs. Among the four lines and polyposis is caused by germline mutations of the 87 HCCs without CTNNB1 mutations, AXIN1 mutations gene.6,49 In colon cancer cell lines containing only mutant were detected in three lines and six mutations in five of APC, a stable b-catenin-hTcf-4 complex was found that the primary HCCs.60 Another study of 73 HCCs and 27 was constitutively active (hTcf-4 is a Tcf family member hepatoblastomas (HBs) found b-catenin mutations in that is expressed in colonic epithelium). Reintroduction around 20% of HCCs and 80% of HBs, and AXIN1 and of wild-type APC removed b-catenin from hTcf-4 and AXIN2 mutations in an additional 10% of HCCs and abrogated the transcriptional activation.50 Constitutive HBs.61 transcription of Tcf target genes, caused by loss of APC Analysis of 17 samples of adenocarcinomas of the function, may be a crucial event in the early transforma- gastro-oesophageal junction with nuclear accumulation tion of colonic epithelium.
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