Journal of Pathology J Pathol 2013; 230: 430–440 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/path.4202 ORIGINAL PAPER Dasatinib inhibits mammary tumour development in a genetically engineered mouse model Saadia A Karim, 1,# Helen Creedon, 2,# Hitesh Patel, 2 Neil O Carragher, 2 Jennifer P Morton, 1 William J Muller, 3 Thomas RJ Evans, 1 Barry Gusterson, 4 Owen J Sansom 1 and Valerie G Brunton 2, * 1 Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK 2 Edinburgh Cancer Research UK Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK 3 Goodman Cancer Research Center, McGill University, Montreal, Canada H3A 1A3 4 Institute of Cancer Sciences, Glasgow University, Glasgow G12 8QQ, UK *Correspondence to: Dr Valerie Brunton, Edinburgh Cancer Research UK Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK. e-mail: v.brunton@ed.ac.uk # These authors contributed equally to this study. 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. Copyright  2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: breast cancer; Src; mouse model; dasatinib Received 1 October 2012; Revised 2 April 2013; Accepted 4 April 2013 No conflicts of interest were declared. Introduction The non-receptor tyrosine kinase Src plays a central role in a number of signalling pathways, integrating cues from both growth factor receptors and integrins, and therefore controls numerous cellular processes involved with the malignant phenotype, including proliferation, migration, invasion, and angiogenesis [1,2]. In addition, it has been known for many years that Src activity and expression are increased in a number of tumour types [3], which has led to the development of small molecule Src kinase inhibitors [4], with numerous phase I/II clinical trials now completed or underway [5–7]. In breast cancer, increased Src activity has been linked to reduced survival [8,9] and Src is known to play a key role in many of the signalling pathways that drive breast cancer development. For example, Src is activated following activation of the oestrogen receptor (ER), while Src can in turn phosphorylate the ER and regulate its activity [10]. Several preclinical studies have reported that combining Src inhibitors with anti-hormonal therapies leads to more effective inhibition of breast cancer growth than seen with the single agents, and in addition can delay the onset of resistance [11–15]. Src is also involved in signalling downstream of the epidermal growth factor receptor (ErbB/HER) family of receptors [16]. ErbB-2 is over- expressed or amplified in around 20% of breast cancers and is associated with poor prognosis and reduced patient survival [17]. Trastuzumab is a monoclonal antibody which targets HER2 and it improves survival in both early and advanced breast cancer, although acquired resistance is emerging as a significant cause Copyright  2013 Pathological Society of Great Britain and Ireland. J Pathol 2013; 230: 430–440 Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com