Breast cancer metastasis to liver and lung is facilitated by Pit-1-CXCL12-CXCR4 axis

Abstract

Development of human tumors is driven by accumulation of alterations in tumor suppressor genes and oncogenes in cells. The POU1F1 transcription factor (also known Pit-1) is expressed in the mammary gland and its overexpression induces profound phenotypic changes in proteins involved in breast cancer progression. Patients with breast cancer and elevated expression of Pit-1 show a positive correlation with the occurrence of distant metastasis and poor overall survival. However, some mediators of Pit-1 actions are still unknown. Here, we show that CXCR4 chemokine receptor and its ligand CXCL12 play a critical role in the pro-tumoral process induced by Pit-1. We found that Pit-1 increases mRNA and protein in both CXCR4 and CXCL12. Knock-down of CXCR4 reduces tumor growth and spread of Pit-1 overexpressing cells in a zebrafish xenograft model. Furthermore, we described for the first time pro-angiogenic effects of Pit-1 through the CXCL12-CXCR4 axis, and that extravasation of Pit-1 overexpressing breast cancer cells is strongly reduced in CXCL12-deprived target tissues. Finally, in breast cancer patients, expression of Pit-1 in primary tumors was found to be positively correlated with CXCR4 and CXCL12, with specific metastasis in liver and lung, and with clinical outcome. Our results suggest that Pit-1-CXCL12-CXCR4 axis could be involved in chemotaxis guidance during the metastatic process, and may represent prognostic and/or therapeutic targets in breast tumors.

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Acknowledgements

This study was supported by Ministerio de Economía y Competividad (SAF2015-69221-R, MINECO/FEDER), and Conselleria de Cultura, Educación e Ordenacion Universitaria (GPC2014/001) to RP-F, and Ministerio de Educacion, FPU14/00548 to AM-O. We want to particularly acknowledge the patients and the BioBank Complejo Hospitalario Universitario de Santiago (CHUS) (PT17/0015/0002), integrated in the Spanish National Biobanks Network for its collaboration, to P. Peñas for providing biological samples, and to M. Fraile for help us with histological analyses.

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Correspondence to Roman Perez-Fernandez.

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Anxo Martinez-Ordoñez and Samuel Seoane contributed equally to this work.

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Martinez-Ordoñez, A., Seoane, S., Cabezas, P. et al. Breast cancer metastasis to liver and lung is facilitated by Pit-1-CXCL12-CXCR4 axis. Oncogene 37, 1430–1444 (2018). https://doi.org/10.1038/s41388-017-0036-8

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