Autocrine Activation of the Wnt/β-Catenin Pathway by CUX1 and GLIS1 in Breast Cancers

Charles Vadnais; Peiman Shooshtarizadeh; Charles V Rajadurai; Robert Lesurf; Laura Hulea; Sayeh Davoudi; Chantal Cadieux; Michael Hallett; Morag Park; Alain Nepveu

doi:10.1242/bio.20148193

Autocrine Activation of the Wnt/β-Catenin Pathway by CUX1 and GLIS1 in Breast Cancers

Biol Open. 2014 Sep 12;3(10):937-46. doi: 10.1242/bio.20148193.

Authors

Affiliations

¹ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
² Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
³ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada McGill Centre for Bioinformatics, McGill University, Montreal, QC H3G 0B1, Canada.
⁴ Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
⁵ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada McGill Centre for Bioinformatics, McGill University, Montreal, QC H3G 0B1, Canada.
⁶ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada Department of Medicine, McGill University, Montreal, QC H3A 1A1, Canada Department of Oncology, McGill University, Montreal, QC H2W 1S6, Canada.
⁷ Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada Department of Medicine, McGill University, Montreal, QC H3A 1A1, Canada Department of Oncology, McGill University, Montreal, QC H2W 1S6, Canada [email protected].

Abstract

Autocrine 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.

Keywords: Breast cancer; Expression profiling; Mouse tumor model; Transcriptional regulation; Wnt/β-Catenin pathway.