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

• Published in: Cellular signalling 2012-09, Vol.24 (9), p.1847-1855
• Main Authors: Eastman, Boryana M., Jo, Minji, Webb, Drue L., Takimoto, Shinako, Gonias, Steven L.
• Format: Article
• Language: English
• Subjects: Activation; Animals; Autonomous; Breast; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; EGF receptor; ERK; Erlotinib Hydrochloride; Estrogen receptor; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - metabolism; Estrogens; Estrogens - deficiency; Estrogens - metabolism; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Humans; Inhibitors; Kinases; Mice; Mice, SCID; Protein Kinase Inhibitors - pharmacology; Quinazolines - pharmacology; Receptors, Urokinase Plasminogen Activator - antagonists & inhibitors; Receptors, Urokinase Plasminogen Activator - genetics; Receptors, Urokinase Plasminogen Activator - metabolism; Signal Transduction - drug effects; Transformations; Tumor Cells, Cultured; uPAR; Urokinase-type plasminogen activator
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2012.05.011

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. ► Increased uPAR expression transforms signaling to ERK, so that it is autonomous of uPA. ► Autonomous uPAR signaling is H-Ras and Rac1-dependent. ► EGFR is an important co-receptor for autonomous uPAR signaling. ► High uPAR expression provides a selection advantage for ERα+ breast cancer cells.