Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities

Abstract

Wnt signaling is a highly conserved signaling pathway that plays a critical role in controlling embryonic and organ development, as well as cancer progression. Genome-wide sequencing and gene expression profile analyses have demonstrated that Wnt signaling is involved mainly in the processes of breast cancer proliferation and metastasis. The most recent studies have indicated that Wnt signaling is also crucial in breast cancer immune microenvironment regulation, stemness maintenance, therapeutic resistance, phenotype shaping, etc. Wnt/β-Catenin, Wnt-planar cell polarity (PCP), and Wnt-Ca²⁺ signaling are three well-established Wnt signaling pathways that share overlapping components and play different roles in breast cancer progression. In this review, we summarize the main findings concerning the relationship between Wnt signaling and breast cancer and provide an overview of existing mechanisms, challenges, and potential opportunities for advancing the therapy and diagnosis of breast cancer.

Keywords: Breast cancer; Canonical/noncanonical Wnt signaling; Drug resistance; Epithelial-mesenchymal transition; Immune microenvironment; Phenotype shaping; Tumoral heterogeneity.

Fig. 1

Canonical Wnt signaling pathway in mammals

Fig. 2

Wnt–PCP signaling pathway in mammals. a Planar cell polarity of the asymmetric transmembrane complexes. b Asymmetric PCP signaling components form transmembrane complexes. c Wnt–PCP signaling pathway in mammals

Fig. 3

Wnt–Ca²⁺ signaling pathway in mammals

Fig. 4

Wnt signaling in breast cancer classification. a Wnt signaling in the histological classification of breast cancer. b Wnt signaling in the molecular classification of breast cancer. (adapted from [272], additional data are based on an open-source database: www.cbioportal.org)

Fig. 5

Wnt signaling in the immune microenvironment of breast cancer. a Schematic representation of the human mammary gland, breast cancer, and an enlarged cross-section of the duct (adapted from [272]). b Tumor microenvironment of breast cancer. c Wnt signaling in the immune microenvironment of breast cancer

Fig. 6

Wnt signaling in the EMT-dependent metastasis of breast cancer. (adapted from [329, 339, 340])

Fig. 7

Wnt signaling in the inter- and intratumoral heterogeneity of breast cancer. (adapted from [349])

Fig. 8

Wnt signaling in breast cancer drug resistance. a Wnt signaling-induced tumoral heterogeneity involves the drug resistance of breast cancer. b The APC transporters P-gp (encoded by ABCB1) and BCRP (encoded by ABCG2), which are involved in drug efflux, are targets of Wnt signaling in breast cancer. c Wnt signaling involves endocrine resistance in breast cancer. The thickness of the arrow represents the relative contribution of each pathway to the overall oxidation of tamoxifen (adapted from [374])

Fig. 9

Selected Wnt signaling inhibitors (Part 1). a Porcupine inhibitors. b Fzd inhibitors. c Wnt/Fzd/LRP inhibitor. d LGR5-specific antibody-drug conjugate. e Dvl inhibitors. f CK1α agonists. g GSK-3β agonist

Fig. 10

Selected Wnt signaling inhibitors (Part 2). a Siah-1 agonist. b β-Catenin destabilizers. c TNKS1/2 inhibitors. d Axin stabilizers. e β- Catenin/TCF disruptors. f β-Catenin/CBP disruptors. g β-Catenin/TBL1 disruptor. h V-ATPase inhibitors. i Wnt signaling inhibitors with an unknown target

Fig. 11

The bipolar seesaw model between canonical and noncanonical Wnt signaling. (some compositional elements of this figure were obtained from https://www.16pic.com and reference [486])