Wnt signaling in human and mouse breast cancer: Focusing on Wnt ligands, receptors and antagonists

Abstract

Wnt proteins, a group of secreted glycoproteins, mainly combine with receptors Frizzled (FZD) and/or low-density-lipoprotein receptor-related proteins 5/6 (LRP5/6), initiating β-catenin-dependent and -independent signaling pathways. These pathways, which can be regulated by some secreted antagonists such as secreted Frizzled-related proteins (SFRP) and dickkopf-related protein (DKK), play a critical role in embryo development and adult homeostasis. Overactivation of Wnt signaling has been implicated in some human diseases including cancer. Wnt transgenic mice provide convincing evidence that Wnt signaling is involved in breast cancer initiation and progression, which is further strengthened by observations on human clinical breast cancer patients and studies on in vitro cultured human breast cancer cells. This review focuses on the roles of Wnt ligands, receptors and antagonists in breast cancer development instead of molecules or signaling transactivating β-catenin independent on Wnt upstream components.

Keywords: DKK; FZD; SFRP; Wnt; β-catenin.

Figure 1

Mouse breast carcinogenesis induced by the activation of the canonical Wnt pathway. CK1, casein kinase 1; DVL, Dishevelled; GSK3β, glycogen synthase kinase 3 beta; LRP5/6, low‐density lipoprotein receptor‐related proteins 5/6; MMTV, mouse mammary tumor virus; TCF/LEF, T‐cell factor/lymphoid enhancer factor

Figure 2

Positive feedback loop between the Rspo/Lgr5 pathway and the Wnt/β‐catenin pathway. LRP5/6, low‐density lipoprotein receptor‐related proteins 5/6; Rspo, R‐spondin

Figure 3

Crosstalk between the transforming growth factor‐beta (TGF‐β) pathway and the Wnt/β‐catenin pathway in the induction of breast cancer epithelial‐mesenchymal transition (EMT). LRP5/6, low‐density lipoprotein receptor‐related proteins 5/6. EMT‐TF, EMT‐transcription factor

Figure 4

Crosstalk between breast cancer cells and mesenchymal fibroblasts in the breast cancer microenvironment. CAF, cancer‐associated fibroblasts; Fb, fibroblasts; T, tumor cells; T‐EMT, tumor cells with epithelial‐mesenchymal transition