Journal article
Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737
SR Oakes, F Vaillant, E Lim, L Lee, K Breslin, F Feleppa, S Deb, ME Ritchie, E Takano, T Ward, SB Fox, D Generali, GK Smyth, A Strasser, DCS Huang, JE Visvader, GJ Lindeman
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2012
Abstract
Overexpression of the prosurvival protein BCL-2 is common in breast cancer. Here we have explored its role as a potential therapeutic target in this disease. BCL-2, its anti-apoptotic relatives MCL-1 and BCL-XL, and the proapoptotic BH3-only ligand BIM were found to be coexpressed at relatively high levels in a substantial proportion of heterogeneous breast tumors, including clinically aggressive basal-like cancers. To determine whether the BH3 mimetic ABT-737 that neutralizes BCL-2, BCL-XL, and BCL-W had potential efficacy in targeting BCL-2-expressing basal-like triple-negative tumors, we generated a panel of primary breast tumor xenografts in immunocompromised mice and treated recipients ..
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Funding Acknowledgements
We are grateful to K. Lowes, B. Pal, J. Corbin, M. Chapman, and the Royal Melbourne Hospital Tissue Bank staff for expert technical assistance; K. Stoev and A. Morcom for animal care; and S. Mihajlovic and E. Tsui for histology support. We thank P. Bouillet for discussions and Abbott Laboratories (S. Rosenberg, S. Elmore, and colleagues) and Genentech (W. Fairbrother) for providing ABT-737 and discussions. Primary tumor samples were provided by the Victorian Cancer Biobank (VCB). This work was supported by the Victorian Government through the Victorian Cancer Agency/Victorian Breast Cancer Research Consortium (J. E. V., G. J. L., and S. B. F.) and an Operational Infrastructure Support grant, the National Health and Medical Research Council Australia (NHMRC; to J. E. V., G. J. L., A. S., and D. C. S. H.) and the Australian Cancer Research Foundation. S.R.O. was supported by the NHMRC and the National Breast Cancer Foundation (NBCF); E. L. by the NHMRC and NBCF; L. L. by the NHMRC and the Cancer Therapeutics CRC; S. D. by the VCB; and A. S., D. C. S. H., J. E. V., and G. J. L. by NHMRC Research Fellowships.