Astrocyte-induced Reelin expression drives proliferation of Her2+ breast cancer metastases

Breast cancer metastasis to the brain develops after a clinical latency of years to even decades, suggesting that colonization of the brain is the most challenging step of the metastatic cascade. However, the underlying mechanisms used by breast cancer cells to successfully colonize the brain's microenvironment remain elusive. Reelin is an archetypal extracellular glycoprotein that regulates migration, proliferation, and lamination of neurons. It is epigenetically silenced in various cancers, and its expression in multiple myelomas is linked to poor patient survival. We found that Reelin expression was low in primary breast cancer tissue. However, its expression was significantly higher in Her2 +  breast cancers metastasizing to the brain. In particular, Reelin was highly expressed in the tumor periphery adjacent to surrounding astrocytes. This augmented Reelin expression was seen in Her2 + metastases, but not in triple negative (TN) primary tumors or in TN breast to brain metastasis cells co-cultured with astrocytes. Furthermore, the elevated expression was sustained in Her2 + cells grown in the presence of the DNA methyltransferase inhibitor 5-azacytidine, indicating epigenetic regulation of Reelin expression. The relative growth and rate of spheroids formation derived from Her2 + primary and BBM cells co-cultured with astrocytes were higher than those of TN primary and BBM cells, and knockdown of both Reelin and Her2 suppressed the astrocyte-induced growth and spheroid forming ability of Her2 + cells. Collectively, our results indicate that within the neural niche, astrocytes epigenetically regulate Reelin expression and its interaction with Her2 leading to increased proliferation and survival fitness.