Cellular and molecular mechanisms involved in breaching of the blood-brian barrier by circulating breast cancer cells

Abstract

Brain metastases are prevalent in lung, melanoma and breast cancers and are associated with high morbidity and mortality. Therefore, targeted treatments and preventative strategies of brain metastasis are needed. Brain metastases of breast cancer confer significant morbidity and appear to be increasing in incidence (~35 %) in subpopulations of metastatic breast cancer patients, particularly those with Her2+ or triple-negative breast cancer (TNBC). Current therapy for brain metastases of breast cancer involves radiation, surgery and chemotherapy. Unfortunately, both disease progression in brain and treatments cause significant patient morbidity, including cognitive defects. The main question is how are circulating breast tumor cells (CBTCs) able to penetrate the blood-brain barrier (BBB) and gain access to the brain parenchyma, forming brain metastases. The BBB is a dynamic and highly selective barrier due to existence of tight junctions and adherens junctions between adjacent brain microvascular endothelial cells (BMECs). Although, the disruption of the BBB by brain metastases of human triple-negative and basal-type breast cancer was observed, very little is known on the cellular and molecular mechanisms involved in the process of CBTC infiltration through the BBB. This review focuses on the BBB and BMECs as well as several biological determinants by which breast tumor cells infiltrate the BBB and activate BMECs, resulting in co-option and colonization of tumor cells in brain.