Wnt-1 was found as an oncogene activated by the Mouse Mammary Tumor Virus in murine breast cancer (Nusse and Varmus, 1982). APC was first isolated as a tumor suppressor gene in human colon cancer (reviewed in Polakis 1997). After establishing that APC and b-catenin bind to each other (Su et al, 1993; Rubinfeld 1993) activating mutations in the human ß-catenin gene were found in human colon cancer and melanomas (Morin et al, 1997) These mutations alter specific b-catenin residues important for GSK3 phosphorylation and stability (see table).
Mutations in the human AXIN1 gene were reported in human hepatocellular carcinomas (Satoh et al, 2000; reviewed by Clevers, 2000). These findings underscore the important predictive value of these pathways: by establishing how genes control signaling (e.g. whether they act as repressors or activators) one can make educated guesses how these gene might contribute to human cancer. A repressor can be a tumor suppressor gene and an activator a dominant oncogene. The same principle applies to other pathways, such as the Hedgehog-Patched pathway and the TGF beta pathway.
TCF1 can also act as a tumor suppressor gene (Roose, 1999), as Tcf1 mutant mice develop adenomas in the gut and mammary glands. Introduction of a mutant APC allele into these mice increases the number of tumors, suggesting that Tcf1 acts as a feedback repressor of target genes of the pathway.
ZNRF3 and RNF3 are transmembrane molecules that down-regulate Wnt signaling. They have E3 ubiquitin ligase activity acting on the Frizzled molecules, leading to turn-over of these receptors (Hao et al, 2012, Koo et al, 2012). Binding of R-Spondin to ZNRF3 has been postulated to down-regulate the activity of the ZNRF3 activity, thereby enhancing Wnt signaling as the Frizzled receptors now become available ((Hao et al, 2012). ZNRF3 and RNF3 are mutated in some tumors (Koo et al, 2012; Jiang et al, 2013).
In 10% of colon tumors, Seshagiri (2012) identified fusion transcripts from gene fusions involving the R-spondin family members RSPO2 and RSPO3. The same group showed later that targeting RSPO3 in a tumor xenograft with a PTPRK-RSPO3-fusion was leading to inhibition of tumor growth and differentiation.
Wnt signaling has been implicated as a local factor in promoting the proliferation of metastatic cells (Malladi et al, 2016)