title: Dasatinib inhibits mammary tumour development in a genetically engineered mouse model.
abstract: 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.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Saadia A
authors.initials: SA
authors.lastname: Karim
authors.forename: Helen
authors.initials: H
authors.lastname: Creedon
authors.forename: Hitesh
authors.initials: H
authors.lastname: Patel
authors.forename: Neil O
authors.initials: NO
authors.lastname: Carragher
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.forename: Thomas Rj
authors.initials: TR
authors.lastname: Evans
authors.forename: Barry
authors.initials: B
authors.lastname: Gusterson
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004742:Enhancer Elements, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007782:Lactoglobulins / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D007782:Lactoglobulins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D051176:beta Catenin; D019061:src-Family Kinases; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000069439:Dasatinib
keywords: Src; breast cancer; dasatinib; mouse model