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The BH3-only protein Bad confers breast cancer taxane sensitivity through a nonapoptotic mechanism

Oncogene volume 29, pages 5381–5391 (2010)Cite this article

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Abstract

Antimitotic agents such as taxanes (paclitaxel and docetaxel) have greatly advanced the treatment of breast cancer, although variable patient response and drug toxicity are major limitations. Lack of validated predictive markers for taxane responsiveness precludes a priori identification of patients who are most likely to respond to treatment; thus, a subset of patients endure toxic side effects with marginal benefit. Mechanistic insights into taxane therapeutic activity may lead to rational therapeutic improvements. In this paper we report that the proapoptotic BH3-only protein Bad has a major role in taxane-induced cell death in vitro, and clinically is a prognostic indicator for overall survival of breast cancer patients after adjuvant taxane chemotherapy. Unexpectedly, Bad did not induce the mitochondrial apoptotic machinery in response to taxane treatment. Instead, Bad indirectly facilitated cell death by stimulating cellular proliferation. As dividing cells are the targets of taxane therapy, Bad-stimulated proliferation may be a marker of taxane sensitivity. Our studies indicate that quantification of Bad protein levels may have value as a diagnostic tool. They also suggest that cells expressing Bad are more sensitive to taxanes because of their altered cell cycle dynamics and reveal a clinically relevant proliferative role of Bad in breast cancer.

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Acknowledgements

We thank Drs Thomas Simmen, Roseline Godbout and Simonetta Sipione for helpful discussions, Ms Yisu Li for assistance with gene expression microarray analysis and Ms Cheryl Santos for excellent technical input. We also thank the anonymous reviewers for insightful suggestions that improved this study. ACC is a recipient of a QEII Graduate Scholarship. DAU is supported by the Mary Johnston Melanoma Research Chair. ISG is a recipient of a Recruitment Award from the Alberta Cancer Research Institute. This work was supported by operating grants from the Alberta Cancer Research Institute and the Canadian Breast Cancer Foundation awarded to ISG.

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  1. A C Craik and R A Veldhoen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada

    A C Craik, R A Veldhoen, M Czernick, T W Buckland, K Kyselytzia & I S Goping

  2. Department of Oncology, School of Cancer, Engineering and Imaging Sciences in Medicine, University of Alberta, Edmonton, Alberta, Canada

    S Ghosh, D A Underhill, J R Mackey & I S Goping

  3. Department of Laboratory Medicine and Pathology, School of Clinical and Laboratory Sciences, University of Alberta, Edmonton, Alberta, Canada

    R Lai & S Damaraju

  4. PolyomX Program, Alberta Health Services, Cross Cancer Institute, Edmonton, Alberta, Canada

    S Damaraju & J R Mackey

  5. Department of Medical Genetics, School of Human Development, University of Alberta, Edmonton, Alberta, Canada

    D A Underhill

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Craik, A., Veldhoen, R., Czernick, M. et al. The BH3-only protein Bad confers breast cancer taxane sensitivity through a nonapoptotic mechanism. Oncogene 29, 5381–5391 (2010). https://doi.org/10.1038/onc.2010.272

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