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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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.
Conflict of interest
The authors declare that they have no competing interests.
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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