beta-Catenin signaling is a critical event in ErbB2-mediated mammary tumor progression
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.
|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.;|
|Publisher Name||CANCER RESEARCH|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/23720052|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11929|