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The pleiotropic effects of TNFα in breast cancer subtypes is regulated by TNFAIP3/A20

Oncogene volume 38, pages 469–482 (2019)Cite this article

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A Correction to this article was published on 13 June 2019

This article has been updated

Abstract

TNFα is a pleiotropic cytokine which fuels tumor cell growth, invasion, and metastasis in some malignancies, while in others it induces cytotoxic cell death. However, the molecular mechanism by which TNFα exerts its diverse effects on breast cancer subtypes remains elusive. Using in vitro assays and mouse xenografts, we show here that TNFα contributes to the aggressive properties of triple negative breast cancer (TNBC) cell lines via upregulation of TNFAIP3(A20). In a striking contrast, TNFα induces a potent cytotoxic cell death in luminal (ER+) breast cancer cell lines which fail to upregulate A20 expression. Overexpression of A20 not only protects luminal breast cancer cell lines from TNFα-induced cell death via inducing HSP70-mediated anti-apoptotic pathway but also promotes a robust EMT/CSC phenotype by activating the pStat3-mediated inflammatory signaling. Furthermore, A20 overexpression in luminal breast cancer cells induces aggressive metastatic properties in mouse xenografts via generating a permissive inflammatory microenvironment constituted by granulocytic-MDSCs. Collectively, our results reveal a mechanism by which A20 mediates pleiotropic effects of TNFα playing role in aggressive behaviors of TNBC subtype while its deficiency results in TNFα-induced apoptotic cell death in luminal breast cancer subtype.

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  • 13 June 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Author notes

  1. Maria Ouzounova

    Present address: Department of Cancer Cell Plasticity, Cancer Research Center of Lyon (CRCL), Lyon, France

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA

    Eunmi Lee, Maria Ouzounova, Raziye Piranlioglu, Minh Thu Ma, Ahmed Chadli, John K. Cowell & Hasan Korkaya

  2. Regenerative and Restorative Research Center (REMER), Medipol University, Istanbul, Turkey

    Mustafa Guzel

  3. Department of Pharmacy, University of Naples “Federico II”, 80134, Naples, Italy

    Daniela Marasco

  4. University of California, San Francisco, USA

    Jason E. Gestwicki & Khaled A. Hassan

  5. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA

    Max S. Wicha

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Correspondence to Hasan Korkaya.

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Lee, E., Ouzounova, M., Piranlioglu, R. et al. The pleiotropic effects of TNFα in breast cancer subtypes is regulated by TNFAIP3/A20. Oncogene 38, 469–482 (2019). https://doi.org/10.1038/s41388-018-0472-0

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