Research Papers:

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

Daniela Rovito, Giulia Gionfriddo, Ines Barone, Cinzia Giordano, Fedora Grande, Francesca De Amicis, Marilena Lanzino, Stefania Catalano, Sebastiano Andò and Daniela Bonofiglio _

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Oncotarget. 2016; 7:65109-65124. https://doi.org/10.18632/oncotarget.11371

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Daniela Rovito1,2, Giulia Gionfriddo1, Ines Barone1, Cinzia Giordano2, Fedora Grande1, Francesca De Amicis1, Marilena Lanzino1, Stefania Catalano1, Sebastiano Andò1,2,*, Daniela Bonofiglio1,*

1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

2Centro Sanitario, University of Calabria, Rende (CS), Italy

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Correspondence to:

Sebastiano Andò, email: [email protected]

Daniela Bonofiglio, email: [email protected]

Keywords: PPARγ, CXCR4, breast cancer, CAF, PPRE

Received: May 09, 2016     Accepted: August 11, 2016     Published: August 18, 2016


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.

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