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Role of Mdm4 in drug sensitivity of breast cancer cells

Oncogene volume 29, pages 2415–2426 (2010)Cite this article

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Abstract

The p53 tumor suppressor protein is frequently mutated in human tumors. It is thought that the p53 pathway is indirectly impaired in the remaining tumors, for example by overexpression of its important regulators Mdm2 and Mdm4, making them attractive targets for the development of anti-cancer agents. Recent studies have suggested that Mdm4 levels determine the sensitivity of tumor cells for anti-cancer therapy. To investigate this possibility, we studied the drug sensitivity of several breast cancer cell lines containing wild-type p53, but expressing different Mdm4 levels. We show that endogenous Mdm4 levels can affect the sensitivity of breast cancer cells to anti-cancer agents, but in a cell line-dependent manner and depending on an intact apoptotic response. Furthermore, treatment with the non-genotoxic agent Nutlin-3 sensitizes cells for doxorubicin, showing that activation of p53 by targeting its regulators is an efficient strategy to decrease cell viability of breast cancer cells. These results confirm a function of Mdm4 in determining the efficacy of chemotherapeutic agents to induce apoptosis of cancer cells in a p53-dependent manner, although additional undetermined factors also influence the drug response. Targeting Mdm4 to sensitize tumor cells for chemotherapeutic drugs might be a strategy to effectively treat tumors harboring wild-type p53.

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Acknowledgements

We thank Dr G Selivanova for providing RITA, Dr A Levine and Dr G Peters for providing anti-Mdm2 and anti-p16 antibodies, respectively. This study was supported by grants from the Association for International Cancer Research (grant 05-273) and by EC FP6 funding (contract 503576) to AG Jochemsen. This publication reflects the authors’ views and not necessarily those of the European Community. The EC is not liable for any use that may be made of the information contained.

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Authors and Affiliations

  1. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

    S Lam, K Lodder, A F A S Teunisse, M J W E Rabelink & A G Jochemsen

  2. Department of Medical Oncology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

    M Schutte

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  1. S Lam
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Correspondence to A G Jochemsen.

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Lam, S., Lodder, K., Teunisse, A. et al. Role of Mdm4 in drug sensitivity of breast cancer cells. Oncogene 29, 2415–2426 (2010). https://doi.org/10.1038/onc.2009.522

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