Targeting the WNT/beta-catenin/TCF/LEF1 axis in solid and haematological cancers: Multiplicity of therapeutic options.
Among aberrantly regulated signalling pathways in cancer the WNT/beta-catenin pathway plays an outstanding role, since it was shown to be critically involved in a wide range of neoplasias. While the underlying mechanisms vary, overexpression of WNTs was found to mediate active signalling in some of these diseases. Other cancers show a mutation in pathway members further downstream, such as APC, Axin or beta-catenin, leading to aberrant signalling activation. Another mechanism initiating activation of WNT/beta-catenin signalling is the silencing of expression of negative WNT/beta-catenin regulators, such as DKK and WIF1, by, for example, promoter hypermethylation. All these mechanisms result in a common consequence, the activation of TCF/LEF1 transcription factors and subsequent target gene expression. Several target genes are known to be key players in tumourigenesis, such as c-myc, cyclin D1 or survivin. The variety of possible underlying mechanisms leading to beta-catenin/TCF/LEF1 activation offers multiple options to target the aberrantly activated pathway in order to prevent target gene expression and/or their gene products to exert their tumourigenic function. Here, we summarise the physiological role of WNT/beta-catenin signalling and the consequences of its aberrant activation during tumourigenesis. Furthermore, we discuss the possible strategies to target this pathway and their potential importance in cancer treatment.
Gehrke
Iris
I
Department I of Internal Medicine, University at Cologne, Kerpener Strasse 62, Cologne 50937, Germany.
Gandhirajan
Rajesh Kumar
RK
Kreuzer
Karl-Anton
KA
D000818:Animals; D015536:Down-Regulation; D019337:Hematologic Neoplasms / Q000628:therapy; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000628:therapy*; D015398:Signal Transduction / Q000235:genetics*; D051822:T Cell Transcription Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics
C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D051822:T Cell Transcription Factor 1; D051153:Wnt Proteins; D051176:beta Catenin