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PMID: 20595387 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

HER2/ErbB2-induced breast cancer cell migration and invasion require p120 catenin activation of Rac1 and Cdc42.

The Journal of biological chemistry ·Vol. 285 ·No. 38 ·2010-09-17 ·Pages 29491-501

Johnson E, Seachrist DD, DeLeon-Rodriguez CM, Lozada KL, Miedler J, Abdul-Karim FW, Keri RA

Abstract

Breast cancers that overexpress the receptor tyrosine kinase ErbB2/HER2/Neu result in poor patient outcome because of extensive metastatic progression. Herein, we delineate a molecular mechanism that may govern this malignant phenotype. ErbB2 induction of migration requires activation of the small GTPases Rac1 and Cdc42. The ability of ErbB2 to activate these small GTPases necessitated expression of p120 catenin, which is itself up-regulated by signaling through ErbB2 and the tyrosine kinase Src. Silencing p120 in ErbB2-dependent breast cancer cell lines dramatically inhibited migration and invasion as well as activation of Rac1 and Cdc42. In contrast, overexpression of constitutively active mutants of these GTPases reversed the effects of p120 silencing. Lastly, ectopic expression of p120 promoted migration and invasion and potentiated metastatic progression of a weakly metastatic, ErbB2-dependent breast cancer cell line. These results suggest that p120 acts as an obligate intermediate between ErbB2 and Rac1/Cdc42 to modulate the metastatic potential of breast cancer cells.

MeSH Terms
Animals Blotting, Western Breast Neoplasms/genetics,metabolism Catenins/genetics,metabolism Cell Line Cell Line, Tumor Cell Movement/genetics,physiology Female Fluorescent Antibody Technique Humans Immunohistochemistry In Vitro Techniques Mice Mice, Nude Receptor, ErbB-2/genetics,metabolism Wound Healing/genetics,physiology cdc42 GTP-Binding Protein/genetics,metabolism rac1 GTP-Binding Protein/genetics,metabolism
Chemicals
Catenins delta catenin Receptor, ErbB-2 cdc42 GTP-Binding Protein rac1 GTP-Binding Protein
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Johnson Emhonta
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Seachrist Darcie D
DeLeon-Rodriguez Carlos M
Lozada Kristen L
Miedler John
Abdul-Karim Fadi W
Keri Ruth A
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M110.136770
Published
2010-09-17
Epub
2010-00-01
Pages
29491-501
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2937981
Subset
IM
Grants
NCI NIH HHS · R01 CA090398 · United States
NCI NIH HHS · T32 CA059366 · United States
External Links
PubMed source DOI: 10.1074/jbc.M110.136770 PMC Full Text View journal details
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