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ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 1  |  Page : 30-36

Treatment with Src inhibitor dasatinib results in elevated metastatic potential in the 4T1 murine mammary carcinoma model


Department of Radiation Oncology, University of Florida, Gainesville, FL, USA

Correspondence Address:
Dr. Veronica S Hughes
2033 Mowry Road, Gainesville, FL 32608
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tme.tme_19_17

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Introduction: The src inhibitor dasatinib has been widely studied as an antimetastatic agent. The aims of this study were to examine the effect of Src inhibition on the metastatic potential of the 4T1 murine mammary carcinoma. Context: Src is a nonreceptor tyrosine kinase well known to contribute to the metastatic potential of tumor cells. It does so through alteration of signaling pathways important to metastasis. Elevated levels of Src are common in many cancer types and have been correlated with tumor progression and poor patient prognosis. Aims: This study examined whether disruption of the Src signaling pathway could inhibit metastasis formation. Settings and Design: The Src inhibitor dasatinib was evaluated in vitro and in vivo using the highly metastatic 4T1 murine mammary adenocarcinoma cell line. Methods: In vitro assays included growth curve, Western blot, migration, and invasion assays. In vivo assays included intradermal and tail vein injection models. Statistical Analysis Used: In vitro data were analyzed using one-way ANOVA with Dunnett's multiple comparisons in GraphPad Prism 6.0. In vivo data were analyzed using GraphPad Prism 6.0, using the Wilcoxon matched pairs test. Results: Dasatinib is effective at inhibiting in vitro phosphorylation of Src, migration and invasion in the 4T1 cell line, as well as angiogenesis in vivo. In vitro treatment with dasatinib impaired the metastatic ability of tumor cells as assessed by a tail vein injection model. However, both the syngeneic BALB/c and the athymic nu/nu mice receiving oral doses of the drug developed significantly higher numbers of 4T1 lung metastases. This effect was neither seen in a different breast carcinoma cell line, the MDA-MB-231-4175-LM2 nor in the murine fibrosarcoma KHT cell line. Conclusions: The 4T1 cell line is not an appropriate model to study Src inhibition.


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