Reelin Deficiency Delays Mammary Tumor Growth and Metastatic Progression

Reelin is a regulator of cell migration in the nervous system, and has other functions in the development of a number of non-neuronal tissues. In addition, alterations in reelin expression levels have been reported in breast, pancreatic, liver, gastric, and other cancers. Reelin is normally expressed in mammary gland stromal cells, but whether stromal reelin contributes to breast cancer progression is unknown. Herein, we used a syngeneic mouse mammary tumor transplantation model to examine the impact of host-derived reelin on breast cancer progression. We found that transplanted syngeneic tumors grew more slowly in reelin-deficient (rl ^{Orl -/-} ) mice and had delayed metastatic colonization of the lungs. Immunohistochemistry of primary tumors revealed that tumors grown in rl ^{Orl -/-} animals had fewer blood vessels and increased macrophage infiltration. Gene expression studies from tumor tissues indicate that loss of host-derived reelin alters the balance of M1- and M2-associated macrophage markers, suggesting that reelin may influence the polarization of these cells. Consistent with this, rl ^{Orl -/-} M1-polarized bone marrow-derived macrophages have heightened levels of the M1-associated cytokines iNOS and IL-6. Based on these observations, we propose a novel function for the reelin protein in breast cancer progression.