Ligand-activated PPARγ downregulates CXCR4 gene expression through a novel identified PPAR response element and inhibits breast cancer progression

Stromal Derived Factor-1a (SDF-1a) and its cognate receptor CXCR4 play a key role in mediating breast cancer cell invasion and metastasis. Therefore, drugs able to inhibit CXCR4 activation may add critical tools to reduce tumor progression, especially in the most aggressive form of the breast cancer disease. Peroxisome ProliferatorActivated Receptor (PPAR) gamma, a member of the nuclear receptor superfamily, has been found to downregulate CXCR4 gene expression in different cancer cells, however the molecular mechanism underlying this effect is not fully understood. Here, we identified a novel PPAR.-mediated mechanism that negatively regulates CXCR4 expression in both epithelial and stromal breast cancer cells. We found that ligand-activated PPAR. downregulated CXCR4 transcriptional activity through the recruitment of the silencing mediator of retinoid and thyroid hormone receptor (SMRT) corepressor onto a newly identified PPAR response element (PPRE) within the CXCR4 promoter in breast cancer cell lines. As a consequence, the PPAR gamma agonist rosiglitazone (BRL) significantly inhibited cell migration and invasion and this effect was PPAR gamma-mediated, since it was reversed in the presence of the PPAR. antagonist GW9662. According to the ability of cancer-associated fibroblasts (CAFs), the most abundant component of breast cancer stroma, to secrete high levels of SDF-1a, BRL reduced migratory promoting activities induced by conditioned media (CM) derived from CAFs and affected CXCR4 downstream signaling pathways activated by CAF-CM. In addition, CAFs exposed to BRL showed a decreased expression of CXCR4, a reduced motility and invasion along with a phenotype characterized by an altered morphology. Collectively, our findings provide novel insights into the role of PPAR gamma in inhibiting breast cancer progression and further highlight the utility of PPAR gamma ligands for future therapies aimed at targeting both cancer and surrounding stromal cells in breast cancer patients.