Faculty Collaboration Database

p38gamma mitogen-activated protein kinase integrates signaling crosstalk between Ras and estrogen receptor to increase breast cancer invasion. Cancer Res 2006 Aug 01;66(15):7540-7

Date

08/04/2006

Pubmed ID

16885352

Pubmed Central ID

PMC2174269

DOI

10.1158/0008-5472.CAN-05-4639

Scopus ID

2-s2.0-33747872178 (requires institutional sign-in at Scopus site)   41 Citations

Abstract

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 p38gamma mitogen-activated protein kinase in Ras transformation in rat intestinal epithelial cells, and here, we show that p38gamma integrates invasive antagonism between Ras and ER to increase human breast cancer invasion without affecting their proliferative activity. Ras positively regulates p38gamma expression, and p38gamma in turn mediates Ras nonmitogenic signaling to increase invasion. Expression of the Ras/p38gamma 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 p38gamma protein, leading to its specific down-regulation in the nuclear compartment. A p38gamma-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 p38gamma specifically integrates their antagonistic activity to stimulate cell invasion. Selective targeting of p38gamma-dependent invasion pathways may be a novel strategy to control breast cancer progression.

Author List

Qi X, Tang J, Loesch M, Pohl N, Alkan S, Chen G

Authors

Guan Chen PhD, MD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Xiao-Mei Qi MD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Breast Neoplasms
Cell Growth Processes
Cell Nucleus
DNA, Neoplasm
Down-Regulation
Gene Expression Regulation, Neoplastic
Humans
Mitogen-Activated Protein Kinase 12
Neoplasm Invasiveness
Phosphorylation
Receptor Cross-Talk
Receptors, Estrogen
Signal Transduction
Transfection
ras Proteins