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Transcription factor c-Myb inhibits breast cancer lung metastasis by suppression of tumor cell seeding

Oncogene volume 37, pages 1020–1030 (2018)Cite this article

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Abstract

Metastasis accounts for most of cancer-related deaths. Paracrine signaling between tumor cells and the stroma induces changes in the tumor microenvironment required for metastasis. Transcription factor c-Myb was associated with breast cancer (BC) progression but its role in metastasis remains unclear. Here we show that increased c-Myb expression in BC cells inhibits spontaneous lung metastasis through impaired tumor cell extravasation. On contrary, BC cells with increased lung metastatic capacity exhibited low c-Myb levels. We identified a specific inflammatory signature, including Ccl2 chemokine, that was expressed in lung metastatic cells but was suppressed in tumor cells with higher c-Myb levels. Tumor cell-derived Ccl2 expression facilitated lung metastasis and rescued trans-endothelial migration of c-Myb overexpressing cells. Clinical data show that the identified inflammatory signature, together with a MYB expression, predicts lung metastasis relapse in BC patients. These results demonstrate that the c-Myb-regulated transcriptional program in BCs results in a blunted inflammatory response and consequently suppresses lung metastasis.

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Acknowledgements

This work was funded by SCOPES/SNF grant IZ73Z0-152361 (L Borsig, L Knopfova and N Volodko). Further by Czech Science Foundation grant 17-08985Y (L Knopfova), National Program of Sustainability II LQ1605-MEYS CR; and ICRC-ERA-HumanBridge/no. 316345 and by the MUNI/0877/2016 project of Grant Agency of Masaryk University. This work was also supported by the SNF grant #310030-152901 (L Borsig). We acknowledge the assistance of the Center for Microscopy and Image Analysis and the Functional Genomic Center at University of Zurich.

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Authors and Affiliations

  1. Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic

    L Knopfová, M Dúcka, T Kučírková, K Souček, J Šmarda & P Beneš

  2. Institute of Physiology, University of Zurich and Zurich Center for Integrative Human Physiology, Zurich, Switzerland

    L Knopfová, E Biglieri, J F Glaus Garzón, P Beneš & L Borsig

  3. International Clinical Research Center, Center for Biological and Cellular Engineering, St. Anne's University Hospital, Brno, Czech Republic

    L Knopfová, M Dúcka, T Kučírková, K Souček & P Beneš

  4. Department of Oncology and Medical Radiology, Danylo Galytsky Lviv National Medical University, Lviv, Ukraine

    N Volodko

  5. Department of Physiology and Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic,

    M Masařík

  6. First Department of Pathological Anatomy, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic

    M Hermanová

  7. Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic,

    K Souček

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  1. L Knopfová
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Knopfová, L., Biglieri, E., Volodko, N. et al. Transcription factor c-Myb inhibits breast cancer lung metastasis by suppression of tumor cell seeding. Oncogene 37, 1020–1030 (2018). https://doi.org/10.1038/onc.2017.392

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