Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

Recent literature highlights the importance of pro-inflammatory cytokines in the biology of breast cancer stem cells (CSCs), unraveling differences with respect to their normal counterparts. Expansion of mammospheres (MS) is a valuable tool for the in vitro study of normal and cancer mammary gland s...

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Bibliographic Details
Published in:Cell death and differentiation 2012-07, Vol.19 (7), p.1208-1219
Main Authors: Papi, A, Guarnieri, T, Storci, G, Santini, D, Ceccarelli, C, Taffurelli, M, De Carolis, S, Avenia, N, Sanguinetti, A, Sidoni, A, Orlandi, M, Bonafé, M
Format: Article
Language:English
Subjects:
Acids
Breast cancer
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell death
Cell Line, Tumor
Cell Survival - drug effects
Cytokines
Estrogens
Female
Genes
Genotype & phenotype
Humans
Inflammation - metabolism
Inflammation - pathology
Interleukin-6 - metabolism
Ligands
Neoplastic Stem Cells - cytology
NF-kappa B - metabolism
Original Paper
Pathology
Phenanthrenes - chemistry
Phenanthrenes - pharmacology
PPAR gamma - agonists
PPAR gamma - metabolism
Pyrimidines - pharmacology
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - metabolism
Receptors, Retinoic Acid - agonists
Receptors, Retinoic Acid - metabolism
Retinoid X Receptors - agonists
Retinoid X Receptors - metabolism
Stem cells
Thiazolidinediones - chemistry
Thiazolidinediones - pharmacology
Tretinoin - chemistry
Tretinoin - pharmacology
Tumor necrosis factor-TNF
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Summary:Recent literature highlights the importance of pro-inflammatory cytokines in the biology of breast cancer stem cells (CSCs), unraveling differences with respect to their normal counterparts. Expansion of mammospheres (MS) is a valuable tool for the in vitro study of normal and cancer mammary gland stem cells. Here, we expanded MSs from human breast cancer and normal mammary gland tissues, as well from tumorigenic (MCF7) and non-tumorigenic (MCF10) breast cell lines. We observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-γ (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells. This phenomenon is paralleled by the hampering of pro-inflammatory Nuclear Factor-κB (NF-κB)/Interleukin-6 (IL6) axis that is hyperactive in breast cancer-derived MS. The hindrance of such pathway associates with the downregulation of MS regulatory genes (SLUG, Notch3, Jagged1) and with the upregulation of the differentiation markers estrogen receptor-α and keratin18. At variance, the PPARα agonist Wy14643 promotes MS formation, upregulating NF-κB/IL6 axis and MS regulatory genes. These data reveal that nuclear receptors agonists (6-OH-11-O-hydroxyphenanthrene, RA, PGZ) reduce the inflammation dependent survival of breast CSCs and that PPARα agonist Wy14643 exerts opposite effects on this phenotype.
ISSN:1350-9047
1476-5403
DOI:10.1038/cdd.2011.207