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p38 Mitogen-Activated Protein Kinase Integrates Signaling Crosstalk between Ras and Estrogen Receptor to Increase Breast Cancer Invasion

Departments of ¹ Radiation Oncology, ² Pharmacology and Experimental Therapeutics, and ³ Pathology and ⁴ Program in Molecular Biology, Loyola University Chicago, Maywood, Illinois and ⁵ Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin

Requests for reprints: Guan Chen, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. Phone: 414-456-8636; Fax: 414-456-6545; E-mail: gchen{at}mcw.edu.

Ras is believed to stimulate invasion and growth by different effector pathways, and yet, the existence of such effectors under physiologic conditions has not been shown. Estrogen receptor (ER), on the other hand, is both anti-invasive and proliferative in human breast cancer, with mechanisms for these paradoxical actions remaining largely unknown. Our previous work showed an essential role of p38 mitogen-activated protein kinase in Ras transformation in rat intestinal epithelial cells, and here, we show that p38 integrates invasive antagonism between Ras and ER to increase human breast cancer invasion without affecting their proliferative activity. Ras positively regulates p38 expression, and p38 in turn mediates Ras nonmitogenic signaling to increase invasion. Expression of the Ras/p38 axis, however, is trans-suppressed by ER that inhibits invasion and stimulates growth also by distinct mechanisms. Analysis of ER and its cytoplasmic localized mutant reveals that ER additionally binds to p38 protein, leading to its specific down-regulation in the nuclear compartment. A p38-antagonistic activity of ER was further shown in a panel of breast cancer cell lines and was shown independent of estrogens by both ER depletion and ER expression. These results revealed that both Ras and ER use distinct pathways to regulate breast cancer growth and invasion, and that p38 specifically integrates their antagonistic activity to stimulate cell invasion. Selective targeting of p38-dependent invasion pathways may be a novel strategy to control breast cancer progression. (Cancer Res 2006; 66(15): 7540-7)

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				X. Qi, N. M. Pohl, M. Loesch, S. Hou, R. Li, J.-Z. Qin, A. Cuenda, and G. Chen p38{alpha} Antagonizes p38{gamma} Activity through c-Jun-dependent Ubiquitin-proteasome Pathways in Regulating Ras Transformation and Stress Response J. Biol. Chem., October 26, 2007; 282(43): 31398 - 31408. [Abstract] [Full Text] [PDF]