Elucidating the role of JAM-B in breast cancer and angiogenesis

Breast cancer is the most common cancer in women in the UK, but how angiogenesis is regulated in breast cancer is unknown. The growth of blood vessels into tumours (angiogenesis) is essential for cancer growth, and anti-angiogenic therapy is an important new strategy to treat cancer. Interestingly, women with Down Syndrome very rarely develop breast cancer, possibly as a result of the presence of three copies of chromosome 21. We will determine how three copies of chromosome 21 suppresses breast cancer angiogenesis. I will focus upon the involvement of a specific chromosome 21 molecule, termed JAM-B, which we already have evidence for a role in angiogenesis. I will use both clinical material and experimental mouse models. This research will help us to understand the disease better and possibly lead to the development of therapies to inhibit breast cancer progression.

Down Syndrome (DS) is a genetic disorder caused by full or partial trisomy of chromosome 21. It presents with many clinical phenotypes including a reduced incidence of solid tumours, in particular breast cancer. This phenotype is thought to occur as a consequence of chromosome 21 ?gene-dosage? effects and suppression of angiogenesis. We will use the transchromosomic (Tc1) mouse model of DS, which expresses 81% of human chromosome 21 (Hsa21) genes, to understand why individuals with DS have a reduced incidence of breast cancer. We will focus on the gene-dosage effect of the JAM-B gene, located on Hsa21. We have compelling preliminary showing that JAM-B, an endothelial cell-specific gene, when overexpressed, is responsible for the inhibition of tumour angiogenesis. We will breed Tc1 mice with JAM-B transgenic mice to generate mice that have 2 copies of JAM-B (Tc1/JAM-B+/-). Using both Tc1 and Tc1/JAM-B+/- mice we will i) examine the gene-dosage effect of JAM-B on breast cancer and angiogenesis and ii) understand the mechanism of action of JAM-B in the regulation of angiogenesis.By using an interdisciplinary approach combining angiogenesis assays with the Tc1 DS model we will identify the gene-dosage effect of JAM-B on breast cancer and tumour angiogenesis.