Trends in Pharmacological Sciences
ReviewGenomic insights into WNT/β-catenin signaling
Section snippets
The canonical WNT pathway
WNT signaling is involved in diverse processes including embryonic development, maintenance of tissue homeostasis, and cancer pathogenesis. The Wingless (WNT) gene was first identified in a random mutagenesis screen in Drosophila melanogaster [1]. Mutations in WNT resulted in loss of wing development and defects in larval segmentation. Subsequent experiments demonstrated that mutations in WNT or ARM (the D. melanogaster β-catenin ortholog) result in a similar segmentation phenotype [1]. Genetic
WNT in development
Early studies implicated WNT signaling as a critical regulator of early vertebrate development [5]. Injection of Xenopus embryos with mRNA encoding positive regulators of the WNT pathway such as WNT1, β-catenin, or LEF1 inhibited formation of the anterior posterior axis and resulted in body axis duplication [5]. In consonance with these observations, β-catenin deletion results in early lethality due to defects in the formation of the anterior posterior axis [5]. Studies in flies revealed that a
WNT activity in cancer pathogenesis
WNT signaling plays an important role in the pathogenesis of several types of human cancers. In a seminal paper, Nusse and Varmus showed that integration of the mouse mammary tumor virus (MMTV) in the mammary epithelium induces mammary tumors by forcing the expression of the proto-oncogene Wnt1 [9]. Moreover, individuals carrying a germline APC mutation develop familial adenomatous polyposis (FAP). Patients affected by FAP develop hundreds of colonic polyps, which progress inevitably to
WNT ligands
WNTs are an evolutionary conserved family of secreted glycoproteins [12]. There are 19 distinct human WNTs that bind specific receptors and activate β-catenin-dependent and -independent pathways [12], in part explaining the diverse pathways and biological processes regulated by WNT signaling [12]. Indeed, forced expression of 14 of the 19 WNT ligands in human cell lines stabilizes β-catenin [13].
Several WNTs have been reported to be involved in cancer initiation and progression through
Functional genomics and WNT signaling
Functional studies in model organisms and cultured cells have been instrumental in deciphering the WNT/β-catenin pathway. The use of large-scale loss-of-function approaches in cancer cell lines have enabled a detailed view of the components directly involved in regulation of the WNT/β-catenin pathway and the various pathways that interact with the WNT/β-catenin pathway in tumor development.
Pharmacological targeting of the WNT pathway
The WNT/β-catenin pathway plays a key role in colon cancer pathogenesis, yet pharmacological targeting has proven to be challenging. Because β-catenin, the major effector of the WNT pathway, drives various context-dependent transcriptional outputs that contribute to diverse phenotypes, effective targeting of β-catenin driven cancers will most likely require inhibition of multiple β-catenin driven pathways.
Several new compounds have recently been described as inhibitors of different nodes of the
Concluding remarks
Although the WNT/β-catenin pathway has been extensively studied both in development and in cancer, recent genomic studies in colon cancer have identified new components and regulators of the canonical WNT/β-catenin pathway. These studies suggest that WNT/β-catenin signaling is more complex than anticipated and may be influenced by context. Further studies will be necessary to understand how WNT/β-catenin signaling contributes to both tumor initiation and progression.
Indeed, the identification
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