Wnt signaling in breast cancer: have we come full circle?

Abstract

Since the original identification of Wnt1 as a mammary oncogene in mouse mammary tumor virus infected mice, questions have been asked about its relevance to human breast cancer. Wnt1 is now known to be one of a large family of Wnt genes encoding structurally similar secreted signaling proteins, several of which are functionally redundant. The principal intracellular signaling pathway activated by these proteins has been elucidated in recent years. Components of this pathway include proto-oncogene products, such as beta-catenin, and tumor suppressor proteins such as APC. Although WNT1 itself has not been implicated in human breast neoplasms, it has been reported that other WNT genes are sometimes overexpressed in human breast cancer and there is growing evidence that downstream components of the Wnt signaling pathway are activated in a significant proportion of breast tumors.

Figure 1

Simplified diagram of the canonical Wnt/β-catenin signaling pathway. Wnt proteins bind to receptors thought to be composed of a Frizzled protein and either of the low density lipoprotein receptor-related proteins LRP5 or LRP6. Signaling via Dishevelled and/or Axin then results in inactivation of a multiprotein complex that normally renders β-catenin unstable. This complex (shown by a dotted rectangle) includes Axin, APC, and glycogen synthase kinase-3β (GSK-3β). By inhibiting this complex, Wnt signals lead to accumulation of β-catenin in the cytosol and its entry into the nucleus. Once in the nucleus, β-catenin binds to proteins of the T-cell factor (Tcf)/lymphoid enhancer factor-1 (Lef1) family and modulates the expression of several target genes. ^* Components of the pathway identified as oncogenes in naturally occurring mouse or human cancers, ^** components identified as tumor suppressors.