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

INTRODUCTION

The src inhibitor Dasatinib has been widely studied as an anti-metastatic 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 non-receptor tyrosine kinase well-known to contribute to the metastatic potential of tumour cells. It does so through alteration of signalling pathways important to metastasis. Elevated levels of Src are common in many cancer types, and have been correlated with tumour progression and poor patient prognosis.

AIMS

This study examined whether disruption of the Src signalling pathway could inhibit metastases formation.

SETTINGS AND DESIGN

The Src inhibitor Dasatinib was evaluated and using the highly metastatic 4T1 murine mammary adenocarcinoma cell line.

METHODS AND MATERIAL

assays included growth curve, western blot, migration, and invasion assays. assays included intradermal and tail vein injection models.

STATISTICAL ANALYSIS USED

data were analysed using one-way ANOVA with Dunnett's multiple comparisons in GraphPad Prism 6.0. data were analysed using GraphPad Prism 6.0, using the Wilcoxon matched pairs test.

RESULTS

Dasatinib is effective at inhibiting phosphorylation of Src, migration and invasion in the 4T1 cell line, as well as angiogenesis . treatment with Dasatinib impaired the metastatic ability of tumour 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 not seen in a different breast carcinoma cell line, the MDA-MB-231-4175-LM2, nor was this effect seen in the murine fibrosarcoma KHT cell line.

CONCLUSIONS

The 4T1 cell line is not an appropriate model to study Src inhibition.