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P38 delta MAPK promotes breast cancer progression and lung metastasis by enhancing cell proliferation and cell detachment

Oncogene volume 36, pages 6649–6657 (2017)Cite this article

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Abstract

The protein p38 mitogen-activated protein kinase (MAPK) delta isoform (p38δ) is a poorly studied member of the MAPK family. Data analysis from The Cancer Genome Atlas database revealed that p38δ is highly expressed in all types of human breast cancers. Using a human breast cancer tissue array, we confirmed elevation in cancer tissue. The breast cancer mouse model, MMTV-PyMT (PyMT), developed breast tumors with lung metastasis; however, mice deleted in p38δ (PyMT/p38δ−/−) exhibited delayed primary tumor formation and highly reduced lung metastatic burden. At the cellular level, we demonstrate that targeting of p38δ in breast cancer cells, MCF-7 and MDA-MB-231 resulted in a reduced rate of cell proliferation. In addition, cells lacking p38δ also displayed an increased cell–matrix adhesion and reduced cell detachment. This effect on cell adhesion was molecularly supported by the regulation of the focal adhesion kinase by p38δ in the human breast cell lines. These studies define a previously unappreciated role for p38δ in breast cancer development and evolution by regulating tumor growth and altering metastatic properties. This study proposes MAPK p38δ protein as a key factor in breast cancer. Lack of p38δ resulted in reduced primary tumor size and blocked the metastatic potential to the lungs.

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Acknowledgements

We thank Dr Eiji Suzuki (Fukushima Medical University), Dr Tatiana Efimova (Washington University), Dr Patricia Watson, Dr Dennis K. Watson and George Washington (Medical University of South Carolina), Dr Hideki Furuya, Dr Toshihiko Kawamori (University of Hawaii), Dr Vincent Yang and members of his laboratory, Mallory Korman, Dr Luisa Escobar-Hoyos, Dr Kai Wang, Dr Chiara Luberto, Dr Achraf Shamsedine, Dr Mónica Garcia-Barros, Dr Jean-Philip Truman, Maria Hernandez, Dr Ashley Snider and Dr Magali Trayssac (Stony Brook University) for helpful technical advice and/or assistance. This work is supported by the National Cancer Institute (R01-CA87584). These studies were supported by NIH Grant CA087584.

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Authors and Affiliations

  1. Department of Medicine, Stony Brook University, Stony Brook, NY, USA

    M Wada, D Canals, M Adada, N Coant, M F Salama, L M Obeid & Y A Hannun

  2. Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA

    D Canals, M Adada, L M Obeid & Y A Hannun

  3. Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt

    M F Salama

  4. Department of Comparative Medicine, Medical University of South Carolina, Charleston, SC, USA

    K L Helke

  5. MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, UK

    J S Arthur

  6. Department of Pathology, Stony Brook University, Stony Brook, NY, USA

    K R Shroyer

  7. Tohoku Medical Megabank Organization and Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan

    K Kitatani

  8. Northport VA Medical Center, Northport, NY, USA

    L M Obeid

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  1. M Wada
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Correspondence to Y A Hannun.

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Wada, M., Canals, D., Adada, M. et al. P38 delta MAPK promotes breast cancer progression and lung metastasis by enhancing cell proliferation and cell detachment. Oncogene 36, 6649–6657 (2017). https://doi.org/10.1038/onc.2017.274

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