title: β-Catenin haploinsufficiency promotes mammary tumorigenesis in an ErbB2-positive basal breast cancer model.
abstract: Aberrant activation of β-catenin through its activity as a transcription factor has been observed in a large proportion of human malignancies. Despite the improved understanding of the β-catenin signaling pathway over the past three decades, attempts to develop therapies targeting β-catenin remain challenging, and none of these targeted therapies have advanced to the clinic. In this study, we show that part of the challenge in antagonizing β-catenin is caused by its dual functionality as a cell adhesion molecule and a signaling molecule. In a mouse model of basal ErbB2 receptor tyrosine kinase 2 (ErbB2)-positive breast cancer (ErbB2KI), which exhibits aberrant β-catenin nuclear signaling, β-catenin haploinsufficiency induced aggressive tumor formation and metastasis by promoting the disruption of adherens junctions, dedifferentiation, and an epithelial to mesenchymal transition (EMT) transcriptional program. In contrast to the accelerated tumor onset observed in the haploid-insufficient ErbB2 tumors, deletion of both β-catenin alleles in the ErbB2KImodel had only a minor impact on tumor onset that further correlated with the retention of normal adherens junctions. We further showed that retention of adherens junctional integrity was caused by the up-regulation of the closely related family member plakoglobin (γ-catenin) that maintained both adherens junctions and the activation of Wnt target genes. In contrast to the ErbB2KIbasal tumor model, modulation of β-catenin levels had no appreciable impact on tumor onset in an ErbB2-driven model of luminal breast cancer [murine mammary tumor virus promoter (MMTV-NIC)]. These observations argue that the balance of junctional and nuclear β-catenin activity has a profound impact on tumor progression in this basal model of ErbB2-positive breast cancer.
authors.affiliation: Goodman Cancer Center, McGill University, Montreal, QC H3A 1A3, Canada.|Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Tung
authors.initials: T
authors.lastname: Bui
authors.affiliation: Goodman Cancer Center, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Babette
authors.initials: B
authors.lastname: Schade
authors.affiliation: Center for Comparative Medicine, University of California, Davis, CA 95616.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.affiliation: Center for Comparative Medicine, University of California, Davis, CA 95616.
authors.forename: Olulanu H
authors.initials: OH
authors.lastname: Aina
authors.affiliation: Goodman Cancer Center, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Virginie
authors.initials: V
authors.lastname: Sanguin-Gendreau
authors.affiliation: Goodman Cancer Center, McGill University, Montreal, QC H3A 1A3, Canada; william.muller@mcgill.ca.|Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.|Faculty of Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
mesh_terms: D000818:Animals; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D057895:Haploinsufficiency; D008175:Lung Neoplasms / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000235:genetics*; D051185:gamma Catenin / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D051176:beta Catenin; D051185:gamma Catenin; C495267:CTNNB1 protein, mouse; C495293:Jup protein, mouse; C524056:Erbb2 protein, mouse
keywords: ErbB2; beta-catenin; breast cancer; cell junction; transgenic model