THE ROLE OF DOCK4 IN CANCER CELL INVASION AND ANGIOGENESIS IN BREAST CANCER BRAIN METASTASES

INTRODUCTION: Development of brain metastatic lesions requires activation of signaling pathways for cancer cell invasion. Metastatic disease is intrinsically linked to endothelial cell activation for brain colonization and angiogenic growth for disease progression. DOCK180 family of Rho guanine nucleotide exchange factors (GEFs) are implicated in invasion, and recent studies show they control blood vessel development. The study aims to elucidate the role of the Rac GEF DOCK4 in breast cancer brain metastases. METHOD: i) Patient samples were analysed for DOCK4 expression levels which were related to histological parameters in primary tumours, and expression levels in brain metastases, ii) the role of DOCK4 in the brain vasculature was studied in heterozygous Dock4 null mice and mouse model of breast cancer brain metastasis, iii) the DOCK4 signalling pathway was delineated using biochemical assays and proteomics approaches. RESULTS: i) Significant correlation was observed between DOCK4 expression and histological grade in primary breast tumours, independent of ER and LN status. There was a trend towards reduced survival in cases with moderate/ strong DOCK4 expression. Moderate/ strong DOCK4 expression was observed in brain metastases specimens. ii) There was significant decrease in brain blood vessel lumen size in Dock4 + /- mice and number of blood vessels with dilated lumens in EO771 intracranial tumours in Dock4 + /- mice. iii) DOCK4 interacts with the Cdc42 GEF DOCK9 and RhoG effector ELMO to control filopodia formation and blood vessel lumen morphogenesis. CONCLUSION: DOCK4 and interaction partners are potential targets and biomarkers in brain metastases through regulation of cancer cell invasion and angiogenesis.