title: β-Catenin signaling is a critical event in ErbB2-mediated mammary tumor progression.
abstract: Although ERBB2 amplification and overexpression is correlated with poor outcome in breast cancer, the molecular mechanisms underlying the aggressive nature of these tumors has not been fully elucidated. To investigate this further, we have used a transgenic mouse model of ErbB2-driven tumor progression (ErbB2(KI) model) that recapitulates clinically relevant events, including selective amplification of the core erbB2 amplicon. By comparing the transcriptional profiles of ErbB2(KI) mammary tumors and human ERBB2-positive breast cancers, we show that ErbB2(KI) tumors possess molecular features of the basal subtype of ERBB2-positive human breast cancer, including activation of canonical β-catenin signaling. Inhibition of β-catenin-dependent signaling in ErbB2(KI)-derived tumor cells using RNA interference impaired tumor initiation and metastasis. Furthermore, treatment of ErbB2(KI) or human ERBB2-overexpressing tumor cells with a selective β-catenin/CBP inhibitor significantly decreased proliferation and ErbB2 expression. Collectively, our data indicate that ERBB2-mediated breast cancer progression requires β-catenin signaling and can be therapeutically targeted by selective β-catenin/CBP inhibitors.
authors.affiliation: Goodman Cancer Centre, McGill Centre for Bioinformatics, McGill University, Montreal, Quebec, Canada.
authors.forename: Babette
authors.initials: B
authors.lastname: Schade
authors.forename: Robert
authors.initials: R
authors.lastname: Lesurf
authors.forename: Virginie
authors.initials: V
authors.lastname: Sanguin-Gendreau
authors.forename: Tung
authors.initials: T
authors.lastname: Bui
authors.forename: Geneviève
authors.initials: G
authors.lastname: Deblois
authors.forename: Sandra A
authors.initials: SA
authors.lastname: O'Toole
authors.forename: Ewan K A
authors.initials: EK
authors.lastname: Millar
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Zardawi
authors.forename: Elena
authors.initials: E
authors.lastname: Lopez-Knowles
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
authors.forename: Michael
authors.initials: M
authors.lastname: Hallett
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D051176:beta Catenin