ADAMTS15 metalloproteinase inhibits breast cancer cell migration

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) family are a group of 19 extracellular, secreted proteases whose known functions include processing of procollagen molecules, cleavage of extracellular matrix proteoglycans and anti-angiogenesis. Our previous studies have shown that ADAMTS15 is a novel predictor of good prognosis in breast cancer; patients whose tumours had high levels of ADAMTS15 expression had an increased relapse-free survival compared with those with lower levels [1]. ADAMTS15 has also emerged as a candidate cancer gene from cancer genome sequencing, and its tumour suppressive function has recently been documented in colorectal cancer [2].

Our study has focused on the cellular effects of overexpression in MCF7 and MDA-MB-231 breast cancer cell lines of full-length wild-type ADAMTS15 and an E-A mutant that lacks metalloproteinase activity. We have generated stable transfectants carrying either an inducible (lentivirus tet-off system) or constitutive vector system. The effects on cell adhesion, migration and proliferation have subsequently been analysed. Proliferation (MTT assay) and adhesion to various matrix components (including collagen, fibronectin and laminin) was not altered with the addition of ADAMTS15. However, ectopic expression (inducible and constitutive) of either full-length ADAMTS15 or the catalytically dead mutant significantly reduced migration in both cell lines. Wild-type ADAMTS15 also enhanced the aggregation of MCF7 cells. These data suggest that ADAMTS15 may exert tumour suppressive effects via modulation of the interactions of breast carcinoma cells with their environment independent of its metalloproteinase activity.