Wnt Signaling in the Breast: From Development to Disease

Abstract

The Wnt cascade is a primordial developmental signaling pathway that plays a myriad of essential functions throughout development and adult homeostasis in virtually all animal species. Aberrant Wnt activity is implicated in embryonic and tissue morphogenesis defects, and several diseases, most notably cancer. The role of Wnt signaling in mammary gland development and breast cancer initiation, maintenance, and progression is far from being completely understood and is rather shrouded in controversy. In this review, we dissect the fundamental role of Wnt signaling in mammary gland development and adult homeostasis and explore how defects in its tightly regulated and intricated molecular network are interlinked with cancer, with a focus on the breast.

Keywords: Wnt; breast; cancer; development; signaling.

FIGURE 1

Wnt ligand secretion. In Wnt secreting cells, immature Wnt proteins are palmitoylated in the endoplasmic reticulum by the porcupine acyl transferase (PORCN). This is an essential step in the Wnt secretory pathway. Lipid-modified Wnt ligands are then transported in secretory vesicles to the plasma membrane with the help of the transmembrane protein Evi/WLS.

FIGURE 2

The Canonical Wnt/β-catenin signaling pathway. In the absence of Wnt ligands or in the presence of Wnt antagonists such as DKK1, WIF1, or SFRPs, the Wnt signaling pathway is kept in the off state by the dynamic degradation of β-catenin mediated by the β-catenin destruction complex. This multiprotein complex is composed of the scaffolding proteins AXIN1/2 and APC and the kinases CK1α and GSK3β. The two kinases sequentially phosphorylate β-catenin, targeting it for proteasomal degradation. Conversely, when Wnt ligands bind the FZD/LRP co-receptor complex, the β-catenin destruction complex is disassembled. Consequently, β-catenin accumulates in the cytoplasm and translocates to the nucleus, where it displaces co-repressors bound to TCF/LEF transcription factors, thereby initiating Wnt-target gene expression. R-spondins can amplify Wnt ligand response and increase cellular sensitivity to Wnt ligands by inhibiting the recycling of FZD receptors.

FIGURE 3

The developing mammary gland and Wnt signaling activity. (A) The first morphogenic event in murine mammary gland embryonic development is the specification of the mammary lines along the anterior-posterior axis of each flank around embryonic day 10.5. On embryonic day 11.5, five pairs of placodes composed of condensed mammary epithelial cells arise from the mammary line. These primordial structures undergo a series of morphological changes until a rudimentary mammary ductal tree is formed at E18.5. (B) TOPGAL Wnt reporter expression during embryonic mammary gland development (Wnt active areas in red) (Chu et al., 2004). (C) TOP lacZ Wnt reporter expression during embryonic mammary gland development (Wnt active areas in red) (Boras-Granic et al., 2006; Boras-Granic and Wysolmerski, 2008).

FIGURE 4

Molecular alterations in Wnt pathway components. Unlike colorectal cancer, direct alterations in β-catenin or β-catenin regulating proteins are virtually inexistent in TNBC. Notwithstanding, a significant proportion of TNBC patients display aberrant levels of β-catenin expression. While there is no clear answer to why, several possible mechanisms have been described to contribute to aberrant β-catenin levels in TNBC. These include the release of β-catenin from plasma membrane pools due to loss of CDH1, mutations or copy number aberrations (illustrative representation–REF: reference, CNV1: duplication of gene B, CNV2: deletion of gene D) in receptors and secreted Wnt agonists and antagonists, hypermethylation of promoters of genes encoding antagonists, expression of truncated antagonist receptors, etc.

FIGURE 5

Overview of Wnt targeting drugs. Several classes of biological and small molecule Wnt-targeting drugs have been developed and studied for anti-cancer activity. The most important include monoclonal antibodies targeting secreted Wnt ligands (Ipafricet) or their receptors (Vantictumab), tankyrase inhibitors (XAV939, JW55, G007-LK, IWR1), disheveled inhibitors (3289–8625, NSC-668036), PORCN inhibitors (LGK974, IWP2), and inhibitors of the β-catenin:TCF/LEF transcriptional complex (iCRT3. iCRT5, iCRT14, GGP049090, PFK115-584).