Investigation of the role of ARFGEF3 in breast to brain metastasis

Abstract

Cancer is the most common cause of morbidity and mortality around the globe and breast cancer is one of the most common malignant tumours. Although the survival rate of breast cancer has improved in recent years, still it can reappear after a few years and can metastasize to the other part of the body. It is relatively common for breast tumours to metastasize to the brain and these metastatic tumours are incurable. Breast to Brain metastasis occurs when the primary breast tumour breaks down and these cancer cells spread to the brain and start proliferating, forming tumours in the brain. A series of recent findings showed that all tumours that metastasize and grow in the brain express neurotransmitter receptors and form synaptic connections with neurons and these pseudo-synapses contribute to tumour proliferation and survival. In our study, Whole exon sequencing data of 26 breast to brain metastatic (BBM) tumours revealed genomic abnormalities in different genes. Sanger sequencing confirmed the mutation of ARFGEF3 in BBM samples. We assume that the loss of ARFGEF3 in a breast cancer cell line contributes to brain metastasis. Further investigation on the role of ARFGEF3 revealed its influence in controlling the expression of lysosomes (LAMP1) in ARFGEF3 knock out MCF7 cell lines. ARFGEF3 role on regulating cell proliferation was also seen crucial as slower proliferation can be a survival gain to resist chemotherapeutic drugs. Further analyses revealed that ARFGEF3 knock out made breast cancer cells switch on certain neurotransmitter receptors which might help them metastases and growth in the brain. The results presented in this study provides a possible mechanism by which breast cancer cells metastasize and proliferate in the brain. The mutation through loss of ARFGEF3 in breast cancer cells gives survival advantage for metastasize and proliferation in the brain. This mechanism of cancer progression can offer an opportunity for the development of new therapeutic drugs.