Peroxisome Proliferator Activated Receptor-α/Hypoxia Inducible Factor-1α Interplay Sustains Carbonic Anhydrase IX and Apoliprotein E Expression in Breast Cancer Stem Cells

Aims: 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-alpha signalling engenders the functional interplay between peroxisome proliferator activated receptor-alpha and hypoxia inducible factor-1 alpha (PPAR alpha/HIF1 alpha). The two proteins promote mammospheres formation and enhance each other expression via miRNA130b/miRNA17-5p-dependent mechanism which is antagonized by PPAR gamma. Further, the PPAR alpha/HIF1 alpha 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. Conclusion: Our data demonstrate the importance of exploring the role of nuclear receptors (PPAR alpha/PPAR gamma) in the regulation of pro-inflammatory pathways, with the aim to thwart breast cancer stem cells functioning.