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beta-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 beta-catenin signaling. Inhibition of beta-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 beta-catenin/CBP inhibitor significantly decreased proliferation and ErbB2 expression. Collectively, our data indicate that ERBB2-mediated breast cancer progression requires beta-catenin signaling and can be therapeutically targeted by selective beta-catenin/CBP inhibitors.

Type Journal
ISBN 1538-7445 (Electronic) 0008-5472 (Linking)
Authors Schade, B. Lesurf, R. Sanguin-Gendreau, V. Bui, T. Deblois, G. O'Toole, S. A. Millar, E. K. Zardawi, S. J. Lopez-Knowles, E. Sutherland, R. L. Giguere, V. Kahn, M. Hallett, M. Muller, W. J.;
Garvan Authors Dr Ewan Millar , Prof Sandra O'Toole
Publisher Name CANCER RES
Published Date 2013-08-01 00:00:00
Published Volume 73
Published Issue 14
Published Pages 4474-87
URL http://www.ncbi.nlm.nih.gov/pubmed/23720052
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?11929_12598/13_Schade_CancerRes_.pdf