title: β-Catenin and NF-κB co-activation triggered by TLR3 stimulation facilitates stem cell-like phenotypes in breast cancer.
abstract: Cancer stem cells (CSCs) are responsible for tumor initiation and progression. Toll-like receptors (TLRs) are highly expressed in cancer cells and associated with poor prognosis. However, a linkage between CSCs and TLRs is unclear, and potential intervention strategies to prevent TLR stimulation-induced CSC formation and underlying mechanisms are lacking. Here, we demonstrate that stimulation of toll-like receptor 3 (TLR3) promotes breast cancer cells toward a CSC phenotype in vitro and in vivo. Importantly, conventional NF-κB signaling pathway is not exclusively responsible for TLR3 activation-enriched CSCs. Intriguingly, simultaneous activation of both β-catenin and NF-κB signaling pathways, but neither alone, is required for the enhanced CSC phenotypes. We have further identified a small molecule cardamonin that can concurrently inhibit β-catenin and NF-κB signals. Cardamonin is capable of effectively abolishing TLR3 activation-enhanced CSC phenotypes in vitro and successfully controlling TLR3 stimulation-induced tumor growth in human breast cancer xenografts. These findings may provide a foundation for developing new strategies to prevent the induction of CSCs during cancer therapies.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.
authors.forename: D
authors.initials: D
authors.lastname: Jia
authors.affiliation: 1] Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5 [2] Life Science College of Northwest A&F University, Yangling, Shaanxi 712100, China.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: 1] Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5 [2] Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.
authors.forename: Y
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.
authors.forename: S
authors.initials: S
authors.lastname: Ooi
authors.affiliation: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: L
authors.initials: L
authors.lastname: Chi
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.
authors.forename: L G
authors.initials: LG
authors.lastname: Filion
authors.affiliation: 1] Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5 [2] Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada [3] Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Figeys
authors.affiliation: 1] Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5 [2] Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada [3] Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D047188:Chalcones / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D047188:Chalcones; D016328:NF-kappa B; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051176:beta Catenin; C436747:cardamonin