PUBLICATION

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

Authors
Martinez-Ordoñez, A., Seoane, S., Cabezas, P., Eiro, N., Sendon-Lago, J., Macia, M., Garcia-Caballero, T., Gonzalez, L.O., Sanchez, L., Vizoso, F., Perez-Fernandez, R.
ID
ZDB-PUB-180113-4
Date
2018
Source
Oncogene   37(11): 1430-1444 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Animals
  • Breast Neoplasms/genetics*
  • Breast Neoplasms/pathology*
  • Cell Movement/genetics
  • Cell Proliferation/genetics
  • Cells, Cultured
  • Chemokine CXCL12/genetics
  • Chemokine CXCL12/physiology*
  • Embryo, Nonmammalian
  • Female
  • Gene Expression Regulation, Neoplastic
  • Human Umbilical Vein Endothelial Cells/physiology
  • Humans
  • Liver Neoplasms/genetics
  • Liver Neoplasms/secondary*
  • Lung Neoplasms/genetics
  • Lung Neoplasms/secondary*
  • MCF-7 Cells
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic/genetics
  • Neovascularization, Pathologic/pathology
  • Receptors, CXCR4/genetics
  • Receptors, CXCR4/physiology*
  • Signal Transduction/physiology
  • Transcription Factor Pit-1/genetics
  • Transcription Factor Pit-1/physiology*
  • Zebrafish
PubMed
29321662 Full text @ Oncogene
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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping