Document Detail


TIMP-1 overexpression does not affect sensitivity to HER2-targeting drugs in the HER2-gene-amplified SK-BR-3 human breast cancer cell line.
MedLine Citation:
PMID:  23334956     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been suggested as a marker of prognosis and response to treatment in breast cancer. In vitro, TIMP-1 can regulate shedding of the extracellular domain of HER2 and signalling via the Akt pathway, and we hypothesize that TIMP-1 therefore can affect sensitivity to the HER2-targeting drugs trastuzumab and lapatinib. SK-BR-3 human breast cancer cells were stably transfected with TIMP-1, characterized with regard to TIMP-1 protein expression, proliferation, and functionality of the secreted TIMP-1, and the sensitivity to trastuzumab and lapatinib was studied in five selected single-cell subclones expressing TIMP-1 protein at various levels plus the parental SK-BR-3 cell line. Both trastuzumab and lapatinib reduced cell viability, as determined by MTT assay, but the sensitivity to the drugs was not associated with the expression level of TIMP-1 protein. Western blotting showed that the activation of Akt, PTEN, and HER2 as well as ADAM10 was similar in all clones. In conclusion, in this model, TIMP-1 overexpression does not affect HER2 cleavage by ADAM10 or signalling via the Akt pathway, and TIMP-1 does not influence sensitivity to trastuzumab and lapatinib.
Authors:
Xiaohong Deng; Louise Fogh; Ulrik Lademann; Vibeke Jensen; Jan Stenvang; Huanming Yang; Nils Brünner; Anne-Sofie Schrohl
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-22
Journal Detail:
Title:  Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine     Volume:  34     ISSN:  1423-0380     ISO Abbreviation:  Tumour Biol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-05-07     Revised Date:  2013-05-08    
Medline Journal Info:
Nlm Unique ID:  8409922     Medline TA:  Tumour Biol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1161-70     Citation Subset:  IM    
Affiliation:
Department of Pathobiology and Sino-Danish Breast Cancer Research Centre, Institute of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. deng@sund.ku.dk
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Monoclonal, Humanized / pharmacology*
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Blotting, Western
Breast Neoplasms / drug therapy*,  metabolism,  pathology
Cell Proliferation / drug effects*
Drug Resistance, Neoplasm / genetics*
Female
Gene Expression Regulation, Neoplastic
Humans
In Situ Hybridization, Fluorescence
PTEN Phosphohydrolase / metabolism
Phosphorylation / drug effects
Proto-Oncogene Proteins c-akt / metabolism
Quinazolines / pharmacology*
Receptor, erbB-2 / genetics*,  metabolism
Tissue Inhibitor of Metalloproteinase-1 / metabolism*
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal, Humanized; 0/Antineoplastic Agents; 0/Quinazolines; 0/TIMP1 protein, human; 0/Tissue Inhibitor of Metalloproteinase-1; 0VUA21238F/lapatinib; EC 2.7.10.1/ERBB2 protein, human; EC 2.7.10.1/Receptor, erbB-2; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase; P188ANX8CK/trastuzumab

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