Methylome analysis reveals Jak-STAT pathway deregulation in putative breast cancer stem cells.
Growing evidence supports the existence of a subpopulation of cancer cells with stem cell characteristics within breast tumors. In spite of its potential clinical implications, an understanding of the mechanisms responsible for retaining the stem cell characteristics in these cells is still lacking. Here, we used the mammosphere model combined with DNA methylation bead arrays and quantitative gene expression to characterize the epigenetic mechanisms involved in the regulation of developmental pathways in putative breast cancer stem cells. Our results revealed that MCF7-derived mammospheres exhibit distinct CpG promoter methylation profiles in a specific set of genes, including those involved in Jak-STAT signaling pathway. Hypomethylation of several gene components of the Jak-STAT pathway was correlated with an increased expression in mammospheres relative to parental cells. Remarkably, cell sorting of the cells with a putative cancer stem cell phenotype (CD44+/CD24 low) suggests a constitutive activation of Jak-STAT pathway in these cells. These results show that Jak-STAT activation may represent a characteristic of putative breast cancer stem cells. In addition, they favor the concept that the expression of cancer stem-like pathways and the establishment and maintenance of defining properties of cancer stem cells are orchestrated by epigenetic mechanisms.
Epigenetics Group, International Agency for Research on Cancer, Lyon, France
Hector
H
Hernandez-Vargas
Maria
M
Ouzounova
Florence
F
Le Calvez-Kelm
Marie-Pierre
MP
Lambert
Sandrine
S
McKay-Chopin
Sean V
SV
Tavtigian
Alain
A
Puisieux
Chantal
C
Matar
Zdenko
Z
Herceg
D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D053612:Janus Kinases / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050791:STAT Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D050791:STAT Transcription Factors; D053612:Janus Kinases