Document Detail


Dasatinib inhibits mammary tumour development in a genetically engineered mouse model.
MedLine Citation:
PMID:  23616343     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Src family kinase activity is elevated in a number of human cancers including breast cancer. This increased activity has been associated with aggressive disease and poor prognosis. Src inhibitors are currently in clinical development with a number of trials currently assessing their activity in breast cancer. However, the results to date have been disappointing and a further evaluation of the preclinical effects of Src inhibitors is required to help establish whether these agents will be useful in the treatment of breast cancer. In this study we investigate the effects of dasatinib, which is a potent inhibitor of Src family kinases, on the initiation and development of breast cancer in a genetically engineered model of the disease. The mouse model utilized is driven by expression of activated ErbB-2 under the transcriptional control of its endogenous promoter coupled with conditional loss of Pten under the control of Cre recombinase expressed by the BLG promoter. We show that daily oral administration of dasatinib delays tumour onset and increases overall survival but does not inhibit the proliferation of established tumours. The striking difference between the dasatinib-treated group of tumours and the vehicle controls was the prominent squamous metaplasia that was seen in six out of 11 dasatinib-treated tumours. This was accompanied by a dramatic up-regulation of both E-cadherin and β-catenin and down-regulation of ErbB-2 in the dasatinib-treated tumours. Dasatinib also inhibited both the migration and the invasion of tumour-derived cell lines in vitro. Together these data support the argument that benefits of Src inhibitors may predominate in early or even pre-invasive disease.
Authors:
Saadia A Karim; Helen Creedon; Hitesh Patel; Neil O Carragher; Jennifer P Morton; William J Muller; Thomas Rj Evans; Barry Gusterson; Owen J Sansom; Valerie G Brunton
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of pathology     Volume:  230     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-07-10     Completed Date:  2013-09-13     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  430-40     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Animals
Antineoplastic Agents / administration & dosage,  pharmacology*
Breast Neoplasms / enzymology,  genetics,  pathology,  prevention & control*
Cadherins / genetics,  metabolism
Cell Differentiation / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Administration Schedule
Enhancer Elements, Genetic
Female
Gene Expression Regulation, Neoplastic
Genes, erbB-2
Integrases / genetics,  metabolism
Lactoglobulins / genetics
Mammary Neoplasms, Experimental / enzymology,  genetics,  pathology,  prevention & control*
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neoplasm Invasiveness
PTEN Phosphohydrolase / deficiency,  genetics
Protein Kinase Inhibitors / administration & dosage,  pharmacology*
Pyrimidines / administration & dosage,  pharmacology*
Signal Transduction / drug effects
Thiazoles / administration & dosage,  pharmacology*
Time Factors
beta Catenin / genetics,  metabolism
src-Family Kinases / antagonists & inhibitors*,  metabolism
Grant Support
ID/Acronym/Agency:
11650//Cancer Research UK; C157/A9148//Cancer Research UK; C6088/A12063//Cancer Research UK
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Cadherins; 0/Catnb protein, mouse; 0/Lactoglobulins; 0/Protein Kinase Inhibitors; 0/Pyrimidines; 0/Thiazoles; 0/beta Catenin; EC 2.7.10.2/src-Family Kinases; EC 2.7.7.-/Cre recombinase; EC 2.7.7.-/Integrases; EC 3.1.3.48/Pten protein, mouse; EC 3.1.3.67/PTEN Phosphohydrolase; RBZ1571X5H/dasatinib

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