Brain metastasis, an important cause of cancer morbidity and mortality, occurs in at least 30% of patients with breast cancer. A key event of brain metastasis is the migration of cancer cells through the blood-brain barrier (BBB). Although preventing brain metastasis is immensely important for survival, very little is known about the early stage of transmigration and the molecular mechanisms of breast tumor cells penetrating the BBB. The brain endothelium plays an important role in brain metastasis, although the mechanisms are not clear. Brain Microvascular Endothelial Cells (BMECs) are the major cellular constituent of the BBB. BMECs are joined together by intercellular tight junctions (TJs) that are responsible for acquisition of highly selective permeability. Failure of the BBB is a critical event in the development and progression of several diseases that affect the CNS, including brain tumor metastasis development. Here, we have delineated the mechanisms of BBB impairment and breast cancer metastasis to the brain. Understanding the molecular mediators that cause changes in the BBB should lead to better strategies for effective treatment modalities targeted to inhibition of brain tumors. 1. Introduction Breast cancer patients often develop metastatic lesions in the brain [1, 2]. The development of CNS metastasis in patients with solid malignancies represents a turning point in the disease process. The prevalence of CNS metastasis from breast cancer may be increasing due to improved systemic therapy for stage IV breast cancer. The standard treatment for multiple brain lesions remains whole-brain radiation for symptom control, with no improvement in survival. The therapy for a single brain metastasis remains either surgery or radiosurgery, with conflicting information as to the benefit of prior whole-brain radiation. To metastasize to the brain, breast cancer cells must attach to microvessel endothelial cells and then invade the blood-brain barrier (BBB), which constitutes the endothelium and the surrounding cells. The BBB is a unique anatomical structure that is mainly defined by tight junctions and adherens junctions between the brain endothelial cells, that strictly regulate the flow of ions, nutrients, and cells into the brain [3, 4]. Compared with endothelial cells from other vascular beds, brain microvascular endothelial cells (BMECs) characteristically have very low permeability to solutes, high electrical resistance, complex tight junctions, and an array of transport systems that both supply the brain with nutrients and eliminates byproducts
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