Wnt signaling in Cancer (July 2005; link is to text below)

Several components of the Wnt signaling pathway have been implicated in human tumors or experimental cancer models.

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 b-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). The role for Frat/GBP in cancer is illustrated by its activation by proviral insertion in mouse lymphomas (Jonkers, 1997). A recent example of the link between cancer and Wnt signaling comes from the identification of the Drosophila gene legless as a homolog of Bcl-9, a gene implicated in B cell malignancies (Kramps, 2002)



Wnt5A, which can act to counteract signaling by other Wnts, appears to be able to act as a tumor suppressor, as mice that are mutant for Wnt5A develop lymphoid malignancies (Liang et al, 2003). There is also evidence that members of the SFRP family are epigenetically inactivated in colon cancer (Suzuki et al, 2004). Because the SFRPs may sequester and inactivate Wnt, loss of SFRP expression may contribute to Wnt activation in cancer.

There are several excellent reviews on Wnt signaling and cancer: Polakis, 2000 and Bienz and Clevers,