Wnt signaling in cancer

Abstract

Aberrant regulation of the Wnt signaling pathway is a prevalent theme in cancer biology. From the earliest observation that Wnt overexpression could lead to malignant transformation of mouse mammary tissue to the most recent genetic discoveries gleaned from tumor genome sequencing, the Wnt pathway continues to evolve as a central mechanism in cancer biology. This article summarizes the evidence supporting a role for Wnt signaling in human cancer. This includes a review of the genetic mutations affecting Wnt pathway components, as well as some of epigenetic mechanisms that alter expression of genes relevant to Wnt. I also highlight some research on the cooperativity of Wnt with other signaling pathways in cancer. Finally, some emphasis is placed on laboratory research that provides a proof of concept for the therapeutic inhibition of Wnt signaling in cancer.

Figure 1.

Tumor suppressors and oncogenes in the Wnt pathway. Diagram of a basic Wnt signaling pathway in which oncogenes are depicted in green and tumor suppressors in red.

Figure 2.

Signaling pathways that cooperate with Wnt signaling. (A) Wnt and prostaglandin signaling. Activation of canonical Wnt signaling drives expression of COX2, which catalyzes production of PGE2, and repression of 15-PDGH, which catalyzes the inactivation of PGE2. PGE2 activates the prostaglandin GPCR receptor EP2 releasing the Gsα subunnit that displaces GSK3 form Axin, resulting in the stabilization of β-catenin. (B) Activation of b-catenin by EGFR. EGFR activity promotes the activation of src and the translocation of PKM2 into the nucleus, in which src phosphorylates residue Y333 on β-catenin. The phosphorylated β-catenin binds PKM2 and the resulting complex associates with TCF in which kinase-active PKM2 displaces HDAC3 to turn on the cyclin D1 target gene.