ADAMTS1-mediated targeting of TSP-1 by PPARδ suppresses migration and invasion of breast cancer cells

Migration and invasion of cancer cells into surrounding tissue is a key stage of cancer metastasis. Here, we show that peroxisome proliferator-activated receptor (PPAR) delta regulates migration and invasion of human breast cancer cells via thrombospondin-1 (TSP-1) and its degrading protease, a disintegrin and metalloprotease domains with thrombospondin motifs 1 (ADAMTS1). Activation of PPAR delta by GW501516, a specific ligand for PPAR delta, led to marked inhibition in the cell migration and TSP-1 expression of breast cancer. These effects were suppressed by small interfering RNA-mediated knock-down of ADAMTS1, indicating that ADAMTS1 is involved in PPAR delta-mediated inhibition of migration and TSP-1 expression in breast cancer cells. In addition, ligand-activated PPAR delta upregulated expression of ADAMTS1 at the transcriptional level via binding of PPAR delta to a direct repeat-1 site within the ADAMTS1 gene promoter. Furthermore, ligand-activated PPAR delta suppressed invasion of breast cancer cells in an ADAMTS1-dependent manner. Taken together, these results demonstrate that PPAR delta suppresses migration and invasion of breast cancer cells by downregulating TSP-1 in a process mediated by upregulation of ADAMTS1.