p38γ mitogen activated protein kinase integrates signaling crosstalk between Ras and estrogen receptor to increase breast cancer invasion

W 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 p3Sy mitogen-activated protein kinase in Ras transformation in rat intestinal epithelial cells, and here, we show that p38 gamma integrates invasive antagonism between Ras and ER to increase human breast cancer invasion without affecting their proliferative activity. Ras positively regulates p38,gamma expression, and p38 gamma in turn mediates Ras nonmitogenic signaling to increase invasion. Expression of the Ras/p38 gamma 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 gamma protein, leading to its specific down-regulation in the nuclear compartment. A p38 gamma-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 gamma specifically integrates their antagonistic activity to stimulate cell invasion. Selective targeting of p3S gamma-dependent invasion pathways may be a novel strategy to control breast cancer progression.