We are trying to establish the roles and mechanisms of Reelin signalling during mammary gland development, identify its effects on ductal growth, and study the downstream signalling pathway in the mammary gland and possible abnormalities in the regulation in breast cancer.

We have been working from the hypothesis that the same molecular framework that enables the mammary ducts to migrate and grow into the surrounding fat pad during puberty and pregnancy might be de-regulated in invasive breast cancer, allowing the tumour to grow and invade surrounding tissue. Genes expressed during these developmental stages may be involved in the control of cell migration, and that the identification of these genes could therefore lead to potential new targets for diagnostics and/or treatment of breast cancer.

Reelin is a 400kDa secreted glycoprotein that is involved in neuronal cell positioning. Reelin binds to the very low-density lipoprotein receptors VLDLR and ApoER2, which then signal down to the adaptor protein Dab1. Naturally occurring deletion mutants in the ligand (‘Reelerorl’), the adaptor protein Dab1 (‘Scrambler’), and engineered double receptor knock-out mice (vldlr/apoer2-/-) all show the same phenotype of incorrect cell positioning during cortical brain development.

We are now trying to establish the roles and mechanisms of Reelin signalling during mammary gland development, identify its effects on ductal growth, and study the downstream signalling pathway in the mammary gland and possible abnormalities in the regulation in breast cancer. Backed by our other recent finding that axonal guidance proteins are up-regulated in the terminal end buds, these studies may reveal a completely novel potential control mechanism for the development of mammary ductal outgrowth by mechanisms normally only associated with neuronal development.