Key signaling nodes in mammary gland development and cancer: β-catenin

Abstract

β-Catenin plays important roles in mammary development and tumorigenesis through its functions in cell adhesion, signal transduction and regulation of cell-context-specific gene expression. Studies in mice have highlighted the critical role of β-catenin signaling for stem cell biology at multiple stages of mammary development. Deregulated β-catenin signaling disturbs stem and progenitor cell dynamics and induces mammary tumors in mice. Recent data showing deregulated β-catenin signaling in metaplastic and basal-type tumors suggest a similar link to reactivated developmental pathways and human breast cancer. The present review will discuss β-catenin as a central transducer of numerous signaling pathways and its role in mammary development and breast cancer.

Figure 1

Canonical and noncanonical Wnt signaling pathways. In the absence of Wnt ligand (left panel), β-catenin is bound by a destruction complex within which Axin and adenomatous polyposis coli (APC) serve as scaffolds. Bound β-catenin is phosphorylated by glycogen synthase kinase-3β (GSK3β) and casein kinase 1 (CK1), then ubiquitinated by beta-transducing repeat-containing protein (β-TrCP) and targeted for proteasomal destruction. Binding of Wnt ligand (right panel) inhibits the destruction complex, allowing β-catenin to accumulate in the cytoplasm and translocate to the nucleus, where it binds Lef/T-cell factor (TCF) transcription factors and activates target genes. In addition, Wnt5a can activate noncanonical signaling pathways in cell-context-specific ways. DKK, Dickkopf; FRP, frizzled-related protein; Lgs, legless; LRP, low-density lipoprotein-related protein; Pygo2, pygopus homolog 2; WIF, Wnt inhibitory factor.

Figure 2

β-Catenin is at the hub of multiple signaling pathways. Many signaling pathways regulate the stability or binding interactions of β-catenin. In the Wnt pathway, glycogen synthase kinase-3β (GSK3β) and casein kinase 1 (CK1) phosphorylate the N-terminal degron sequence of β-catenin to facilitate its destruction. The phosphatidylinositol-3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) pathways also impinge upon β-catenin phosphorylation by regulating GSK3β activity. In addition, p53 induces the degradation of β-catenin through protein interactions involving Seven in absentia homolog 1 (Siah1), Siah interacting protein (SIP) and EBV-induced G-protein coupled receptor (Ebi), resulting in ubiquitination and degradation of β-catenin. Pin1 binds to β-catenin phosphorylated on S246P to prevent its association with adenomatous polyposis coli (APC). In the NF-κB pathway, IκB kinase (IKK)α and IKKβ phosphorylate β-catenin throughout the protein to activate and inhibit transcription, respectively, although the N-terminus is essential for IKKα regulation. Some proteins, such as those within the transforming growth factor beta (TGFβ) pathway and Sox17, regulate β-catenin in the nucleus by modulating its interaction with transcriptional co-activators Tcf/Lef. Other proteins, like enhancer of zeste homolog 2 (EZH2), interact with β-catenin to promote its translocation into the nucleus. A number of tyrosine kinases phosphorylate (both membrane bound and cytosolic) β-catenin to prevent its binding to the cadherin complex at the cell membrane. Src, epidermal growth factor receptor (EGFR), and erythroblastic leukemia viral oncogene-2 (ErbB2) have been shown or implicated to phosphorylate β-catenin on Y654, while Abelson tyrosine kinase (Abl) phosphorylates Y489. β-TrCP, beta-transducing repeat-containing protein; DKK, Dickkopf; Lgs, legless; LRP, low-density lipoprotein-related protein; MAPK, mitogen-activated protein kinase; NLK, Nemo-like kinase; Pygo2, pygopus homolog 2; sFRP, secreted frizzled-related protein; WIF, Wnt inhibitory factor.

Figure 3

Hypothetical model for paracrine activation of β-catenin signaling in the mammary gland. Progesterone receptor (PR) induces Wnts and receptor activator of NF-κB ligand (RANKL). These paracrine factors bind to their respective receptors low-density lipoprotein-related protein (LRP)5/6 and RANK in basal cells. β-catenin signaling in this cell type induces stem cell amplification and branching. Transforming growth factor beta (TGFβ) signaling within stromal cells restrains ductal morphogenesis by inducing Wnt5a. Wnt5a antagonizes canonical Wnt signaling, possibly via noncanonical Wnt pathways. β-Catenin signaling in luminal progenitors is essential for alveologenesis. As luminal cells lack Wnt receptors, however, it is likely that β-catenin signaling is induced in this cell-type by Wnt-independent mechanisms.