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Published online July 30, 2007
doi:10.1083/jcb.200701092
The Journal of Cell Biology, Vol. 178, No. 3, 425-436
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Lester et al.
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Article

uPAR induces epithelial–mesenchymal transition in hypoxic breast cancer cells



Robin D. Lester, Minji Jo, Valérie Montel, Shinako Takimoto, and Steven L. Gonias

Department of Pathology, University of California, San Diego, La Jolla, CA 92093

Correspondence to Steven L. Gonias sgonias{at}ucsd.edu

Hypoxia activates genetic programs that facilitate cell survival; however, in cancer, it may promote invasion and metastasis. In this study, we show that breast cancer cells cultured in 1.0% O2 demonstrate changes consistent with epithelial–mesenchymal transition (EMT). Snail translocates to the nucleus, and E-cadherin is lost from plasma membranes. Vimentin expression, cell migration, Matrigel invasion, and collagen remodeling are increased. Hypoxia-induced EMT is accompanied by increased expression of the urokinase-type plasminogen activator receptor (uPAR) and activation of cell signaling factors downstream of uPAR, including Akt and Rac1. Glycogen synthase kinase-3ß is phosphorylated, and Snail expression is increased. Hypoxia-induced EMT is blocked by uPAR gene silencing and mimicked by uPAR overexpression in normoxia. Antagonizing Rac1 or phosphatidylinositol 3-kinase also inhibits development of cellular properties associated with EMT in hypoxia. Breast cancer cells implanted on chick chorioallantoic membranes and treated with CoCl2, to model hypoxia, demonstrate increased dissemination. We conclude that in hypoxia, uPAR activates diverse cell signaling pathways that cooperatively induce EMT and may promote cancer metastasis.

R.D. Lester and M. Jo contributed equally to this paper.

Abbreviations used in this paper: CAM, chorioallantoic membrane; DN, dominant-negative; EMT, epithelial–mesenchymal transition; EpoR, erythropoietin receptor; ERK, extracellular signal-regulated kinase; GSK-3ß, glycogen synthase kinase-3ß; HIF, hypoxia-inducible factor; HPRT-1, hypoxanthine phosphoribosyltransferase 1; PI3K, phosphatidylinositol 3-kinase; qPCR, quantitative PCR; sh, short hairpin; uPA, urokinase-type plasminogen activator; uPAR, uPA receptor; VEGF, vascular endothelial growth factor.


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