Document Detail


RNAi-mediated downregulation of uPAR synergizes with targeting of HER2 through the ERK pathway in breast cancer cells.
MedLine Citation:
PMID:  20063318     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Overexpression of urokinase plasminogen activator receptor (uPAR) or HER2 (erbB-2) in breast cancer is associated with a poor prognosis. We previously reported that gene amplification and overexpression of HER2 and uPAR occur in 70% of HER2-amplified tumor cells from blood or tissue of patients with breast cancer. In this study, we first examined whether depletion of HER2 and uPAR synergized in suppression of the growth of breast cancer cells that overexpress both HER2 and uPAR (SKBR3 and ZR 751). The results showed that depletion of either HER2 or uPAR by RNA interference suppressed cell growth and induced cell apoptosis, but that these effects were significantly enhanced in cells depleted of both HER2 and uPAR. Mechanistic analysis demonstrated that silencing of HER2 and uPAR caused suppression of MAPK signal pathways, resulting in decrease of ERK activity and prompting a high p38/ERK activity ratio. The level of the phosphorylated form of ERK was decreased in cells depleted of HER2, uPAR or both, and the effect in cells depleted of both is the most evident. Moreover, downregulation of uPAR synergized with trastuzumab to suppress the growth and induce apoptosis of SKBR3 and ZR 751 cells. uPAR RNAi significantly enhanced the effect of trastuzumab on inhibition of MAPK signal pathways. In conclusion, targeting HER2 and uPAR has a synergistic inhibitory effect on breast cancer cells. Our results provide evidence that simultaneous downregulation of HER2 and uPAR may offer an effective tool for breast cancer therapy.
Authors:
Changfei Li; Sheng Cao; Zhen Liu; Xin Ye; Lizhao Chen; Songdong Meng
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  127     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-08-10     Completed Date:  2010-09-13     Revised Date:  2013-05-08    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1507-16     Citation Subset:  IM    
Affiliation:
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Monoclonal / pharmacology
Antibodies, Monoclonal, Humanized
Apoptosis
Breast Neoplasms / genetics*,  metabolism,  pathology,  physiopathology
Cell Cycle / drug effects
Cell Division
Cell Line, Tumor
Down-Regulation
Extracellular Matrix / pathology
Extracellular Signal-Regulated MAP Kinases / metabolism*
Female
Gene Expression Regulation, Neoplastic
Genetic Vectors
Humans
Plasmids
RNA Interference / physiology*
Receptor, erbB-2 / drug effects,  genetics,  physiology*
Receptors, Urokinase Plasminogen Activator / genetics*
Sincalide / metabolism
Transfection
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Receptors, Urokinase Plasminogen Activator; 25126-32-3/Sincalide; EC 2.7.10.1/ERBB2 protein, human; EC 2.7.10.1/Receptor, erbB-2; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; P188ANX8CK/trastuzumab

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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