Novel Functions for Reelin Signaling in Mammary Gland Development and Breast Cancer Progression

The reelin signaling pathway is a critical regulator of cell migration and positioning throughout the central nervous system. Recent studies identified non-neuronal functions for reelin, and reported alterations in reelin expression in cancers. It is not known whether the reelin signaling pathway plays a role in the development of the mammary gland or in progression of breast cancer. Using mice with mutations in reelin and Disabled-1 (Dab1), the intracellular adaptor protein activated in response to the reelin signal, we showed that the reelin signaling pathway is required for correct ductal patterning during mammary gland morphogenesis. Reelin and Dab1 are expressed in the developing and the mature mammary duct in a complementary pattern. Mutations in reelin or Dab1 resulted in delayed ductal elongation and disorganized mammary epithelium in mice. Mammary epithelial cells exhibited decreased migration in response to exogenous reelin in a Dab1-dependent manner in vitro. Using a syngeneic mouse mammary tumor transplantation model, we examined the effect of host-derived reelin on breast cancer progression. We found that transplanted tumors grew and metastasized more slowly in reelin-deficient mice. Tumors grown in reelin-deficient animals had fewer blood vessels and increased macrophage infiltration. Loss of host-derived reelin altered the balance of M1- and M2-associated macrophage markers in primary tumors, suggesting that reelin may influence the polarization of tumor-associated macrophages. These results indicated an important function for the reelin protein in progression of breast cancer. Furthermore, we found that several alternatively spliced variants of Dab1 exist in the developing and the mature mammary gland. In addition, we showed that alternative splicing of Dab1 is spatially and temporally regulated during puberty, pregnancy, and lactation. Taken together, our findings suggest that the reelin signaling pathway is an essential regulator of mammary gland development and has critical functions in progression of breast cancer