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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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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DOI: https://doi.org/10.1038/onc.2017.392
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