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Breast Cancer Metastasis to Liver and Lung Is Facilitated by Pit-1-CXCL12-CXCR4 Axis

Breast Cancer Metastasis to Liver and Lung Is Facilitated by Pit-1-CXCL12-CXCR4 Axis

Anxo Martinez-Ordoñez, Samuel Seoane, Pablo Cabezas, Noemi Eiro, Juan Sendon-Lago, Manuel Macia, Tomas Garcia-Caballero, Luis O Gonzalez, Laura Sanchez, Francisco Vizoso, Roman Perez-Fernandez

Oncogene. 2018 Mar;37(11):1430-1444.

PMID: 29321662

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP53501410	Pit-1		53501-41-0	Price

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