A new study shows that breast cancer metastasis to the brain usually occurs after metastasis to other organs because cells must be capable of not only general extravasation but also of passing through the blood-brain barrier.
Breast cancer metastasis to the brain typically occurs after metastasis to other organs, possibly because the metastasizing cells must be capable of not only general extravasation but also of passing through the blood-brain barrier (BBB). Using gene expression analysis of breast cancer cells that exhibit specificity for brain colonization, Joan Massagué and colleagues present evidence that supports this hypothesis.
The authors inoculated immunodeficient female mice with two cell lines derived from patients with advanced breast cancer (CN34 and MDA-MB-231 cells) and then isolated populations of these cells that colonized the brain. After a second round of selection, they showed that these brain metastatic derivative (BrM2) cells had an increased ability to metastasize to the brain.
They identified 243 genes the expression of which was deregulated in both CN34-BrM2 and MDA-MB-231-BrM2 cells. Of these genes, the expression of 17 correlated with brain metastasis in a cohort of 368 patients with breast cancer. Interestingly, none of these 17 genes had previously been shown to be associated with bone, liver or lymph node metastases. However, 6 genes had been shown to correlate with lung metastasis. This supports previous studies that have shown an association between pulmonary and cerebral metastasis in breast cancer.
The authors focused on the shared genes encoding cyclooxygenase 2 (COX2) and epidermal growth factor receptor (EGFR) ligands (heparin-binding EGF (HBEGF) in the brain and epiregulin (EREG) in the lungs). COX2 synthesizes prostaglandin, which can increase BBB permeability, and short hairpin RNA (shRNA) against COX2 increased brain metastasis-free survival in mice injected with either of the BrM2 cell lines. EGFR and its ligands influence cell motility and invasion, and inhibition of EGFR with cetuximab also inhibited brain metastasis in mice. Furthermore, transmigration of the BrM2 cells in an in vitro model of the BBB was inhibited by COX2 shRNA, cetuximab or HBEGF shRNA. Given that brain metastases occur late in breast cancer progression, the authors tested the hypothesis that additional unique metastatic mediators could be upregulated to help cells pass through the BBB. A further 26 candidate genes were identified, and the authors focused their attention on a gene normally expressed only in the brain: the 
-2,6-sialyltransferase ST6GALNAC5. ST6GALNAC5 mRNA was increased in both BrM2 cell lines and in additional brain metastatic isolates. How might a sialyltransferase affect metastasis? These enzymes mediate sialylation, which is involved in cell-cell interactions. Indeed, the authors found that the adhesion of CN34-BrM2 cells to brain endothelial cells was inhibited by ST6GALNAC5 shRNA. These cells also exhibited reduced BBB transmigration in vitro and brain metastasis in mice, which was further reduced by cetuximab treatment. Moreover, expression of ST6GALNAC5 in an MDA-MB-231 derivative cell line that normally metastasizes to the lungs increased in vitro BBB transmigration and brain infiltration in mice.
These data shed some light on the poorly understood mechanisms that underlie breast cancer metastasis to the brain. It is hoped that further study of these and other genes associated with brain metastasis will provide candidate therapeutic targets.
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