The role of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-15 (ADAMTS-15) in Breast Cancer

Breast cancer is the most common cancer in women and in 2008 accounted for 8% of UK cancer related deaths. A poor prognosis is particularly conferred upon individuals with evidence of metastatic breast cancer. With some studies noting that at least 70% of patients dying with breast cancer have evidence of metastatic disease. In order to develop novel therapeutic strategies a greater understanding of breast cancer tumourigenesis and metastasis is required. Metalloproteinases were implicated as key drivers of metastasis through their ability to degrade the components of the extracellular matrix. This perspective is now superseded with evidence highlighting the involvement of metalloproteinases in an array of biological roles, from maintaining tissue homeostasis to angiogenesis, and importantly these roles can have tumour suppressive effects. Several metalloproteinases from the A Disintegrin and Metalloproteinase with thrombospondin motifs (ADAMTS) family are candidate tumour suppressors, including ADAMTS-15. In the context of breast cancer relatively high levels of ADAMTS-15 expression had previously been associated with increased relapse free survival. However the functional consequences of ADAMTS-15 expression in breast cancer are unknown and are the focus of this thesis. ADAMTS-15 reduced the migration of MDA-MB-231 and MCF-7 cells, in a metalloproteinase-independent manner. This anti-migratory effect likely involves syndecan-4, since modulation of syndecan-4 expression and signalling attenuated this effect. In contrast to its effects on cell migration, only wildtype ADAMTS-15 exhibited an anti-angiogenic effect in in vitro and ex vivo models of angiogenesis. In experimental metastasis assays, both ADAMTS-15 and E362A (metalloproteinase inactive form of ADAMTS-15) reduced metastasis of MDA- MB-231 cells to the liver, though paradoxically, ADAMTS-15 but not E362A enhanced lung colonisation. Taken together these studies demonstrate for the first time that extracellular ADAMTS-15 has multiple tissue context-dependent actions on breast tumour pathophysiology, some of which require its proteolytic activity whereas others do not.