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 bo... More
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.
