β-Catenin signaling is a critical event in ErbB2-mediated mammary tumor progression.
Date
2013-07ICR Author
Author
Schade, B
Lesurf, R
Sanguin-Gendreau, V
Bui, T
Deblois, G
O'Toole, SA
Millar, EKA
Zardawi, SJ
Lopez-Knowles, E
Sutherland, RL
Giguère, V
Kahn, M
Hallett, M
Muller, WJ
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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http://cancerres.aacrjournals.org/content/73/14/4474Collections
Subject
Cell Line, Tumor
Animals
Humans
Mice
Breast Neoplasms
Mammary Neoplasms, Experimental
Disease Progression
Receptor, erbB-2
Signal Transduction
Cell Proliferation
Transcription, Genetic
Down-Regulation
Gene Expression Regulation, Neoplastic
Female
beta Catenin
MCF-7 Cells
Research team
Endocrinology
Language
eng
License start date
2013-07
Citation
Cancer research, 2013, 73 (14), pp. 4474 - 4487