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Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer

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Abstract

The last three decades have seen significant progress in our understanding of the role of the pro-survival protein BCL-2 and its family members in apoptosis and cancer. BCL-2 and other pro-survival family members including Mcl-1 and BCL-XL have been shown to have a key role in keeping pro-apoptotic ‘effector’ proteins BAK and BAX in check. They also neutralize a group of ‘sensor’ proteins (such as BIM), which are triggered by cytotoxic stimuli such as chemotherapy. BCL-2 proteins therefore have a central role as guardians against apoptosis, helping cancer cells to evade cell death. More recently, an increasing number of BH3 mimetics, which bind and neutralize BCL-2 and/or its pro-survival relatives, have been developed. The utility of targeting BCL-2 in hematological malignancies has become evident in early-phase studies, with remarkable clinical responses seen in heavily pretreated patients. As BCL-2 is overexpressed in ~75% of breast cancer, there has been growing interest in determining whether this new class of drug could show similar promise in breast cancer. This review summarizes our current understanding of the role of BCL-2 and its family members in mammary gland development and breast cancer, recent progress in the development of new BH3 mimetics as well as their potential for targeting estrogen receptor-positive breast cancer.

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Acknowledgements

We thank P Maltezos for assistance with the figures, G Lessene for advice and F Vaillant for helpful comments on the manuscript. We apologize to authors whose contributions have not been cited due to space limitations. Our research in this area is supported by grants from the NHMRC (1016701, 1040978), National Breast Cancer Foundation (NC-13-21, NT-13-06), the Victorian Cancer Agency (TRP13041) and the Victorian Government. DM is supported by an Early Career Fellowship from the National Breast Cancer Foundation (ECF-13-06), JEV by an Australia Fellowship and GJL by a Research Fellowship from the NHMRC (1078730).

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Correspondence to G J Lindeman.

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DM, JEV and GJL are employees of The Walter and Eliza Hall Institute, which receives commercial income and research funding from Genentech and AbbVie, and also collaborates with and receives research funding from Servier. The Royal Melbourne Hospital (Melbourne Health) will receive research funds from AbbVie for an investigator-initiated study on ABT-199 in breast cancer (ISRCTN98335443) where GJL is lead investigator and SWL and JEV are co-investigators. GJL has served on an Advisory Board for AbbVie and Genentech.

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Merino, D., Lok, S., Visvader, J. et al. Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer. Oncogene 35, 1877–1887 (2016). https://doi.org/10.1038/onc.2015.287

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  • DOI: https://doi.org/10.1038/onc.2015.287

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