Characterising a novel signalling cascade involved in the development of breast cancer brain metastasis


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Chiara Galloni1,Teklu Egnuni1,Renu Gahlaut1,Michael Grant1,Valerie Speirs1,Mihaela Lorger1,Georgia Mavria1
1University of Leeds

Abstract

Background

Brain metastases are incurable largely due to limited understanding of the cellular and molecular mechanisms that drive the metastatic process. Breast cancer is the second most frequent cause of brain metastases, with secondary brain tumour occurring in 10-16% of the patients. Our team is working to elucidate the role of the guanine nucleotide exchange factor for the small GTPase Rac1, DOCK4, in the brain tumour microenvironment and the process of metastasis, and to assess whether its expression levels have prognostic value for the risk of brain metastasis in breast cancer patients. Our studies may help to identify a new therapeutic target and potential prognostic biomarkers for breast cancer brain metastasis.

Method

The prognostic value of DOCK4 expression levels for the risk of breast cancer metastasis was assessed by analysing patient samples. Furthermore, immunoblot analysis showed that DOCK4 expression was higher in breast cancer cells capable of metastasising to the brain when compared to parental breast cancer cells. Additionally, mice were injectedeither into the carotid artery or intracranially with DOCK4 depleted breast cancer cells in order to investigate the role of DOCK4 in the process of extravasation and colonisation into the brain.

Results

Our research identified DOCK4 as a key player in promoting the extravasation of breast cancer cells to the brain tissue. However, DOCK4 does not appear to be necessary for the establishment of brain secondary tumour. Ongoing in vitrostudies are focusing on the characterisation of DOCK4-dependent signalling cascade essential for the extravasation process.  

Conclusion

These findings show that DOCK4 might be implicated in the extravasation of breast cancer cells from the brain blood vessels to the surrounding tissue. DOCK4 may represent a valid target for the prevention of brain metastasis and its activity and function may be targeted by small molecule inhibitors.