title: Ligand-activated PPARγ downregulates CXCR4 gene expression through a novel identified PPAR response element and inhibits breast cancer progression.
abstract: Stromal Derived Factor-1α (SDF-1α) 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 Proliferator-Activated Receptor (PPAR) γ, 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 PPARγ-mediated mechanism that negatively regulates CXCR4 expression in both epithelial and stromal breast cancer cells. We found that ligand-activated PPARγ 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 PPARγ agonist rosiglitazone (BRL) significantly inhibited cell migration and invasion and this effect was PPARγ-mediated, since it was reversed in the presence of the PPARγ 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-1α, 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 PPARγ in inhibiting breast cancer progression and further highlight the utility of PPARγ ligands for future therapies aimed at targeting both cancer and surrounding stromal cells in breast cancer patients.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.|Centro Sanitario, University of Calabria, Rende (CS), Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rovito
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Gionfriddo
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.affiliation: Centro Sanitario, University of Calabria, Rende (CS), Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Fedora
authors.initials: F
authors.lastname: Grande
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Amicis
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Lanzino
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.|Centro Sanitario, University of Calabria, Rende (CS), Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008024:Ligands; D047495:PPAR gamma / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements / Q000235:genetics*
chemical_list: C527276:CXCR4 protein, human; D008024:Ligands; D047495:PPAR gamma; D019718:Receptors, CXCR4
keywords: CAF; CXCR4; PPARγ; PPRE; breast cancer