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A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells

Oncogene volume 26, pages 4656–4667 (2007)Cite this article

Abstract

The zinc-finger protein A20/TNFAIP3, an inhibitor of nuclear factor-κB (NF-κB) activation, has been shown to protect MCF-7 breast carcinoma cells from TNFα-induced apoptosis. As estrogen receptor (ER) status is an important parameter in the development and progression of breast cancer, we analysed the effect of 17β-estradiol (E2) treatment on the expression of A20. We found that A20 is a new E2-regulated gene, whose expression correlates with ER expression in both cell lines and tumor samples. With the aim of investigating the impact of A20 expression on MCF-7 cells in response to ER ligands, we established stably transfected-MCF-7 cells overexpressing A20 (MCF-7-A20). These cells exhibited a phenotype of resistance to the 4-hydroxy-tamoxifen cytostatic and pro-apoptotic actions and of hyper-response to E2. Dysregulations in bax, bcl2, bak, phospho-bad, cyclin D1, cyclin E2, cyclin D2 and cyclin A2 proteins expression were shown to be related to the resistant phenotype developed by the MCF-7-A20 cells. Interestingly, we found that A20 was also overexpressed in MVLN and VP tamoxifen-resistant cell lines. Furthermore, high A20 expression levels were observed in more aggressive breast tumors (ER-negative, progesterone receptor-negative and high histological grade). These overall findings strongly suggest that A20 is a key protein involved in tamoxifen resistance, and thus represents both a new breast cancer marker and a promising target for developing new strategies to prevent the emergence of acquired mechanisms of drug resistance in breast cancer.

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Acknowledgements

We are grateful to the Val d’Aurelle Hospital (Montpellier, France) for providing tumor breast samples. We thank Dr P Roux for providing pTK-RL and pCIneo plasmids, Dr HD McCallum for sending the VP cells, Dr E Badia for providing the ERE-Luc plasmid, the MVLN, the CL6.8 and CL6.32 cells, and H Valles and V Denis for technical support. We thank Dr SL Salhi for presubmission editorial assistance. This work was supported by grants from the Ligue Nationale Contre le Cancer (Comité de l’Ardèche, Comité de la Saône et Loire), the Groupement des Entreprises Françaises dans la Lutte Contre le Cancer (Montpellier, France) and the Association pour la Recherche sur le Cancer (ARC, France). JA Vendrell was supported by a fellowship from the Ligue Nationale Contre le Cancer (France).

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  1. CNRS UMR 5160, Centre de Pharmacologie et Biotechnologie pour la Santé, Faculté de Pharmacie, Montpellier, France

    J A Vendrell & N Mechti

  2. Faculté de Pharmacie de Lyon, ISBP, Université of Claude Bernard Lyon 1, Lyon, France

    S Ghayad & P A Cohen

  3. INSERM UMR 590, Lyon, France

    S Ghayad, S Ben-Larbi, C Dumontet & P A Cohen

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  1. J A Vendrell
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Correspondence to P A Cohen.

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Vendrell, J., Ghayad, S., Ben-Larbi, S. et al. A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells. Oncogene 26, 4656–4667 (2007). https://doi.org/10.1038/sj.onc.1210269

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