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

• Published in: Cell death and differentiation Vol. 19; no. 7; pp. 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: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2012; Nature Publishing Group
• Subjects: 631/136/532/71; 631/250/256; 631/45/612/388; 692/699/67/1347; Acids; Apoptosis; Biochemistry; Biomedical and Life Sciences; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Biology; Cell Cycle Analysis; Cell death; Cell Line, Tumor; Cell Survival - drug effects; Cytokines; Estrogens; Female; Genes; Genotype & phenotype; Humans; Inflammation - metabolism; Inflammation - pathology; Interleukin-6 - metabolism; Life Sciences; 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; Italy; nuclear receptor; cancer stem cells; PPAR; retinoid; inflammation
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2011.207

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- κ B (NF- κ B)/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 PPAR α agonist Wy14643 promotes MS formation, upregulating NF- κ B/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 PPAR α agonist Wy14643 exerts opposite effects on this phenotype.