Wnt5a as an effector of TGFβ in mammary development and cancer - PubMed (original) (raw)

Review

Wnt5a as an effector of TGFβ in mammary development and cancer

Rosa Serra et al. J Mammary Gland Biol Neoplasia. 2011 Jun.

Abstract

Wnt5a is a member of the Wingless-related/MMTV-integration family of secreted growth factors, which are involved in a wide range of cellular processes. Wnt signaling can be broadly divided into two categories the canonical, ß-catenin-dependent pathway and the non-canonical ß-catenin-independent pathway. Wnt5a is a non-canonical signaling member of the Wnt family. Loss of Wnt5a is associated with early relapse of invasive breast cancer, increased metastasis, and poor survival in humans. It has been shown that TGF-ß directly regulates expression of Wnt5a in mammary gland and that Wnt5a mediates the effects of TGF-ß on branching during mammary gland development. Here we review the evidence suggesting Wnt5a acts as an effector of TGF-ß actions in breast cancer. It is suggested that the tumor suppressive functions of TGF-ß involve Wnt5a-mediated antagonism of Wnt/ß-catenin signaling and limiting the stem cell population. Interactions between TGF-ß and Wnt5a in metastasis appear to be more complex, and may depend on specific cues from the microenvironment as well as activation of specific intracellular signaling pathways.

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Figures

Figure 1

Wnt signaling pathways. Wnt signaling can be broadly divided into two categories: canonical, β-catenin dependent signaling and non-canonical, β-catenin independent signaling. The most well characterized of the non-canonical signals are the Planar Cell Polarity (PCP) pathway and Wnt/Ca + 2 pathway. PCP and Wnt/Ca signaling have been shown to regulate cell migration

Figure 2

Antagonism of Wnt/β-catenin signaling by TGF-β and Wnt5a. Wnt is a secreted factor that binds to frizzled receptors on basal cells, enabling β-catenin to escape destruction and translocate into the nucleus to associate with the transcription factors, TCF/LEF. Upon association, transcription of genes responsible for proliferation and stem cell maintenance, such as c-myc, tcf4, and axin2, is stimulated. We propose that TGF-β acting through Wnt5a antagonizes Wnt-β-catenin signaling through a yet unknown mechanism thus limiting the stem cell population

Figure 3

Roles of Wnt5a in tumor metastasis. Wnt5a is a secreted protein, which could act both in autocrine and paracrine ways to affect tumor cells and their microenvironment. Wnt5a may act to inhibit metastasis through increased activity of Ddr1 and inhibition of migration. Wnt5a can also promote metastasis, depending on the context of the microenvironment. In this case tumor cells regulate expression of Wnt5a in tumor associated macrophages. Wnt5a then regulates activities in both the tumor cell and the macrophage resulting in increased invasion. F: Fibroblast, L: Lymphocyte, M: Microphage

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Wnt5a as an effector of TGFβ in mammary development and cancer - PubMed (original) (raw)