The Wnt/β-catenin signaling pathway: a potential therapeutic target in the treatment of triple negative breast cancer

Abstract

Breast cancer continues to be a serious health problem particularly in developed countries. Of particular concern is triple negative breast cancer (TNBC) which does not respond well to standard hormone therapy and is associated with poor overall patient prognosis. Recent studies indicate that Wnt/β-catenin signaling is particularly activated in TNBC, such that the Wnt receptor frizzled-7 (FZD7) and the Wnt co-receptor LRP6 were found to be up regulated in TNBC. In addition, it has been demonstrated that transcriptional knockdown of LRP6 or FZD7 in TNBC cells suppressed tumor growth in vivo. Furthermore, salinomycin, a selective breast cancer stem cell killer, was recently demonstrated to be an inhibitor of Wnt/β-catenin signaling by inducing LRP6 degradation. Therefore, the Wnt/β-catenin signaling pathway and particularly the Wnt receptors on the cell surface may serve as novel therapeutic targets for the treatment of TNBC.

Fig. 1.

The Wnt/β-catenin signaling pathway. (A) In the absence of interaction between Wnts and LRP5/6, β-catenin levels are efficiently regulated by a complex containing APC, axin, and GSK3β. This complex promotes phosphorylation of β-catenin by Ck1 and GSK3β (P). Phosphorylated β-catenin becomes multi-ubiquitinated (Ub) and subsequently degraded by the 26S proteasome. (B) In the presence of Wnt binding to LRP5/6 and FZD, phosphorylation and degradation of β-catenin is blocked, which results in β-catenin accumulation and the association of β-catenin with TCF transcription factors. The TCF-β-catenin complexes bind to DNA and activate Wnt target genes together with various transcriptional repressors or activators.