Peroxisome proliferator activated receptor-α/hypoxia inducible factor-1α interplay sustains carbonic anhydrase IX and apoliprotein E expression in breast cancer stem cells.
OBJECTIVE
Cancer stem cell biology is tightly connected to the regulation of the pro-inflammatory cytokine network. The concept of cancer stem cells "inflammatory addiction" leads to envisage the potential role of anti-inflammatory molecules as new anti-cancer targets. Here we report on the relationship between nuclear receptors activity and the modulation of the pro-inflammatory phenotype in breast cancer stem cells.


METHODS
Breast cancer stem cells were expanded as mammospheres from normal and tumor human breast tissues and from tumorigenic (MCF7) and non tumorigenic (MCF10) human breast cell lines. Mammospheres were exposed to the supernatant of breast tumor and normal mammary gland tissue fibroblasts.


RESULTS
In mammospheres exposed to the breast tumor fibroblasts supernatant, autocrine tumor necrosis factor-α signalling engenders the functional interplay between peroxisome proliferator activated receptor-α and hypoxia inducible factor-1α (PPARα/HIF1α). The two proteins promote mammospheres formation and enhance each other expression via miRNA130b/miRNA17-5p-dependent mechanism which is antagonized by PPARγ. Further, the PPARα/HIF1α interplay regulates the expression of the pro-inflammatory cytokine interleukin-6, the hypoxia survival factor carbonic anhydrase IX and the plasma lipid carrier apolipoprotein E.


CONCLUSIONS
Our data demonstrate the importance of exploring the role of nuclear receptors (PPARα/PPARγ) in the regulation of pro-inflammatory pathways, with the aim to thwart breast cancer stem cells functioning.
Department of Biological, Geological, and Environmental Sciences, University of Bologna, Bologna, Italy.
Alessio
A
Papi
Gianluca
G
Storci
Tiziana
T
Guarnieri
Sabrina
S
De Carolis
Sara
S
Bertoni
Nicola
N
Avenia
Alessandro
A
Sanguinetti
Angelo
A
Sidoni
Donatella
D
Santini
Claudio
C
Ceccarelli
Mario
M
Taffurelli
Marina
M
Orlandi
Massimiliano
M
Bonafé
D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001057:Apolipoproteins E; D017077:Culture Media, Conditioned; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C554019:MIRN130 microRNA, human; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D047493:PPAR alpha; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; D002256:Carbonic Anhydrases