title: PPARγ and RXR ligands disrupt the inflammatory cross-talk in the hypoxic breast cancer stem cells niche.
abstract: Cancer stem cells (CSCs) are affected by the local micro-environment, the niche, in which inflammatory stimuli and hypoxia act as steering factors. Here, two nuclear receptors (NRs) agonists, i.e. pioglitazone (PGZ), a ligand of peroxisome proliferator activated receptor-γ, and 6-OH-11-O-hydroxyphenanthrene (IIF), a ligand of retinoid X receptors, were investigated for their capability to interference with the cross-talk between breast CSCs and the niche compartment. We found that IIF potentiates the ability of PGZ to hamper the mammospheres-forming capability of human breast tumours and MCF7 cancer cells, reducing the expression of CSCs regulatory genes (Notch3, Jagged1, SLUG, Interleukin-6, Apolipoprotein E, Hypoxia inducible factor-1α and Carbonic anhydrase IX). Notably, these effects are not observed in normal-MS obtained from human breast tissue. Importantly, NRs agonists abolish the capability of hypoxic MCF7 derived exosomes to induce a pro-inflammatory phenotype in mammary glands fibroblasts. Moreover, NRs agonist also directly acts on breast tumour associated fibroblasts to downregulate nuclear factor-κB pathway and metalloproteinases (MMP2 and MMP9) expression and activity. In conclusion, NRs agonists disrupt the inflammatory cross-talk of the hypoxic breast CSCs niche.
authors.affiliation: Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Papi
authors.forename: Sabrina
authors.initials: S
authors.lastname: De Carolis
authors.forename: Sara
authors.initials: S
authors.lastname: Bertoni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Storci
authors.forename: Virginia
authors.initials: V
authors.lastname: Sceberras
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.forename: Mario
authors.initials: M
authors.lastname: Taffurelli
authors.forename: Marina
authors.initials: M
authors.lastname: Orlandi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonafé
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008024:Ligands; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D047495:PPAR gamma / Q000378:metabolism*; D010616:Phenanthrenes / Q000494:pharmacology; D000077205:Pioglitazone; D020239:Receptor Cross-Talk / Q000187:drug effects; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D055153:Stem Cell Niche / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C575663:6-OH-11-O-hydroxyphenanthrene; D000951:Antigens, Neoplasm; D001057:Apolipoproteins E; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D016328:NF-kappa B; D047495:PPAR gamma; D010616:Phenanthrenes; D047488:Retinoid X Receptors; D045162:Thiazolidinediones; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D000077205:Pioglitazone