Schade, B., Lesurf, R., Sanguin-Gendreau, V., Bui, T., Deblois, G., O'Toole, S. A., Millar, E. K. A., Zardawi, S. J., Lopez-Knowles, E., Sutherland, R. L., Giguere, V., Kahn, M., Hallett, M., Muller, W. J. (2013) beta-Catenin Signaling Is a Critical Event in ErbB2-Mediated Mammary Tumor Progression. CANCER RESEARCH, 73 (14). pp. 4474-4487. ISSN 0008-5472

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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. (C) 2013 AACR.

Item Type:	Article
All Authors:	Schade, B., Lesurf, R., Sanguin-Gendreau, V., Bui, T., Deblois, G., O'Toole, S. A., Millar, E. K. A., Zardawi, S. J., Lopez-Knowles, E., Sutherland, R. L., Giguere, V., Kahn, M., Hallett, M., Muller, W. J.
Additional Information:	ISI Document Delivery No.: 183NR Times Cited: 0 Cited Reference Count: 54 Schade, Babette Lesurf, Robert Sanguin-Gendreau, Virginie Bui, Tung Deblois, Genevieve O'Toole, Sandra A. Millar, Ewan K. A. Zardawi, Sara J. Lopez-Knowles, Elena Sutherland, Robert L. Giguere, Vincent Kahn, Michael Hallett, Michael Muller, William J. Terry Fox Team [020002]; NIH [PO1 2PO1CA099031-06A1]; CIHR [MOP 93525]; NIH MMHC grant; CRC Chair in Molecular Oncology; National Health and Medical Research Council [535903, 427601]; Cancer Institute New South Wales [10/TPG/1-04]; Sydney Catalyst Translational Research Centre [11/TRC/1-02]; Australia and New Zealand Breast Cancer Trials Group; Australian Cancer Research Foundation; Sydney Breast Cancer Foundation; RT Hall Trust; Petre Foundation; Novartis; [10/CRF/1-07] This work was supported by grants from Terry Fox Team 020002, NIH PO1 2PO1CA099031-06A1, CIHR MOP 93525 (W.J. Muller), and NIH MMHC grant. W.J. Muller is supported by CRC Chair in Molecular Oncology. The National Health and Medical Research Council (Program Grant 535903 to R. L. Sutherland; Fellowship 427601 to R. L. Sutherland), the Cancer Institute New South Wales (Translational Program Grant 10/TPG/1-04 to R.L. Sutherland, E.K.A. Millar, and S.A. O'Toole); Sydney Catalyst Translational Research Centre 11/TRC/1-02 (R.L. Sutherland); Fellowship 10/CRF/1-07 (S.A. O'Toole), the Australia and New Zealand Breast Cancer Trials Group (S.A. O'Toole and R.L. Sutherland), the Australian Cancer Research Foundation (R.L. Sutherland), the Sydney Breast Cancer Foundation (S.A. O'Toole), the RT Hall Trust (R.L. Sutherland) and the Petre Foundation (R.L. Sutherland).S.A. O'Toole has Commercial Research Grant from Novartis, honoraria from Speakers Bureau of Lilly Oncology, and is a consultant/advisory board member of Roche. M. Kahn has ownership interest (including patents) in Prism BioLab and is a consultant/advisory board member of Prism BioLab. No potential conflicts of interest were disclosed by the other authors. Amer assoc cancer research Philadelphia
Uncontrolled Keywords:	human-breast-cancer gene-expression elevated expression prognostic value basal phenotype transgenic mice mouse models cyclin d1 tumorigenesis transcription
Research teams:	ICR divisions > Breast Cancer Research > Gene Function ICR divisions > Molecular Pathology > Gene Function
Depositing User:	Barry Jenkins
Date Deposited:	19 Aug 2013 08:44
Last Modified:	23 Dec 2014 15:16
URI:	http://publications.icr.ac.uk/id/eprint/12653

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