A transformation in the mechanism by which the urokinase receptor signals provides a selection advantage for estrogen receptor-expressing breast cancer cells in the absence of estrogen.

Abstract

Binding of urokinase-type plasminogen activator (uPA) to its receptor, uPAR, in estrogen receptor-α (ERα) expressing breast cancer cells, transiently activates ERK downstream of FAK, Src family kinases, and H-Ras. Herein, we show that when uPAR is over-expressed, in two separate ERα-positive breast cancer cell lines, ERK activation occurs autonomously of uPA and is sustained. Autonomous ERK activation by uPAR requires H-Ras and Rac1. A mutated form of uPAR, which does not bind vitronectin (uPAR-W32A), failed to induce autonomous ERK activation. Expression of human uPAR or mouse uPAR but not uPAR-W32A in MCF-7 cells provided a selection advantage when these cells were deprived of estrogen in cell culture for two weeks. Similarly, MCF-7 cells that express mouse uPAR formed xenografts in SCID mice that survived and increased in volume in the absence of estrogen supplementation, probably reflecting the pro-survival activity of phospho-ERK. Autonomous uPAR signaling to ERK was sensitive to the EGFR tyrosine kinase inhibitors, Erlotinib and Gefitinib. The transition in uPAR signaling from uPA-dependent and transient to autonomous and sustained is reminiscent of the transformation in ErbB2/HER2 signaling observed when this gene is amplified in breast cancer. uPAR over-expression may provide a pathway for escape of breast cancer cells from ERα-targeting therapeutics.

• Authors: Boryana M Eastman, Minji Jo, Drue L Webb, Shinako Takimoto, Steven L Gonias
• Journal: Cellular signalling (Cell Signal) Vol. 24 Issue 9 Pg. 1847-55 (Sep 2012) ISSN: 1873-3913 [Electronic] England
• PMID: 22617030 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Estrogen Receptor alpha
• Estrogens
• Protein Kinase Inhibitors
• Quinazolines
• Receptors, Urokinase Plasminogen Activator
• Erlotinib Hydrochloride
• Extracellular Signal-Regulated MAP Kinases
• Gefitinib

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• Erlotinib Hydrochloride
• Estrogen Receptor alpha (antagonists & inhibitors, metabolism)
• Estrogens (deficiency, metabolism)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Female
• Gefitinib
• Humans
• Mice
• Mice, SCID
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• Receptors, Urokinase Plasminogen Activator (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured