Abstract
ABSTRACTAutocrine activation of the Wnt/β-catenin pathway occurs in several cancers, notably in breast tumors, and is associated with higher expression of various Wnt ligands. Using various inhibitors of the FZD/LRP receptor complex, we demonstrate that some adenosquamous carcinomas that develop in MMTV-CUX1 transgenic mice represent a model for autocrine activation of the Wnt/β-catenin pathway. By comparing expression profiles of laser-capture microdissected mammary tumors, we identify Glis1 as a transcription factor that is highly expressed in the subset of tumors with elevated Wnt gene expression. Analysis of human cancer datasets confirms that elevated WNT gene expression is associated with high levels of CUX1 and GLIS1 and correlates with genes of the epithelial-to-mesenchymal transition (EMT) signature: VIM, SNAI1 and TWIST1 are elevated whereas CDH1 and OCLN are decreased. Co-expression experiments demonstrate that CUX1 and GLIS1 cooperate to stimulate TCF/β-catenin transcriptional activity and to enhance cell migration and invasion. Altogether, these results provide additional evidence for the role of GLIS1 in reprogramming gene expression and suggest a hierarchical model for transcriptional regulation of the Wnt/β-catenin pathway and the epithelial-to-mesenchymal transition.
Highlights
The Wnt/b-catenin signaling pathway plays an important role in the development and regeneration of several tissues by stimulating the growth of stem cells and multipotential progenitors (MacDonald et al, 2009; Nusse, 2008)
Elevated Wnt Gene Expression in Mammary Tumor Cells Leads to Autocrine Activation of the Wnt/b-catenin Pathway To be able to investigate whether elevated Wnt gene expression in mammary tumor virus (MMTV)-CUX1 mammary tumors leads to autocrine activation of the Wnt/b-catenin pathway, we first established cell lines from the p75-80 adenosquamous carcinoma and the p75-534 solid carcinoma
As niclosamide promotes Frizzled1 internalization and down-regulates Dvl-2 expression (Chen et al, 2009b), whereas sFRP1/2 and SOST/DKK inhibit activation of the FRP-LRP5/6 receptor by respectively binding to Wnt ligands or the LRP5/6 receptor (Dann et al, 2001; Hoang et al, 1996; Hsieh et al, 1999; Semenov and He, 2006), these results indicate that elevated TCF/b-catenin transcriptional activity in p75-80 cells results from autocrine activation of the Wnt pathway
Summary
The Wnt/b-catenin signaling pathway plays an important role in the development and regeneration of several tissues by stimulating the growth of stem cells and multipotential progenitors (MacDonald et al, 2009; Nusse, 2008). Wnts are secreted extracellular proteins that trigger a wide range of cellular responses upon receptor binding and activation. Most organisms contain multiple Wnt genes which initiate distinct cellular pathways, namely the canonical Wnt/b-catenin pathway, the planar cell polarity pathway, or the Wnt/calcium pathway. Wnt proteins initiate the canonical pathway by binding and activating the Frizzled (Fzd) and LRP5/6 receptors. Activation of these receptors induces the dissociation of b-catenin from the degradation complex. Many of the TCF/b-catenin target genes code for Wnt signaling components that are capable of enhancing or antagonizing Wnt pathway activity (MacDonald et al, 2009). Activation of the FZD and LRP5/6 receptors can be inhibited by two types of secreted proteins. Secreted Frizzled-related proteins (sFRPs) and the Wnt inhibitory factor (WIF) bind Wnt proteins and prevent their interaction with LRP5/6 receptors, whereas Dickkopf (DKK) and sclerostin (SOST) compete with Wnt for binding to LRP5 and LRP6 (Dann et al, 2001; Hoang et al, 1996; Hsieh et al, 1999; Semenov and He, 2006)
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