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

• Published in: Oncogene Vol. 37; no. 8; pp. 1020 - 1030
• Main Authors: Knopfová, L, Biglieri, E, Volodko, N, Masařík, M, Hermanová, M, Glaus Garzón, J F, Dúcka, M, Kučírková, T, Souček, K, Šmarda, J, Beneš, P, Borsig, L
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 22.02.2018
• Subjects: Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; c-Myb protein; Care and treatment; Cell Proliferation; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Development and progression; Extravasation; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Humans; Inflammation; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Monocyte chemoattractant protein 1; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Paracrine signalling; Prognosis; Proto-Oncogene Proteins c-myb - genetics; Proto-Oncogene Proteins c-myb - metabolism; Stroma; Transcription factors; Tumor cells; Tumor Cells, Cultured; Tumor Microenvironment; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.392

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.