Premium
Dasatinib inhibits mammary tumour development in a genetically engineered mouse model
Author(s) -
Karim Saadia A,
Creedon Helen,
Patel Hitesh,
Carragher Neil O,
Morton Jennifer P,
Muller William J,
Evans Thomas RJ,
Gusterson Barry,
Sansom Owen J,
Brunton Valerie G
Publication year - 2013
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4202
Subject(s) - dasatinib , proto oncogene tyrosine protein kinase src , cancer research , breast cancer , cancer , erbb , pten , biology , kinase , medicine , cre recombinase , genetically modified mouse , tyrosine kinase , transgene , receptor , signal transduction , pi3k/akt/mtor pathway , gene , microbiology and biotechnology , genetics
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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.