Brief Reports: A Distinct DNA Methylation Signature Defines Breast Cancer Stem Cells and Predicts Cancer Outcome

Abstract

Self-renewal and differentiation are two epigenetic programs that regulate stem cells fate. Dysregulation of these two programs leads to the development of cancer stem cells (CSCs). Recent evidence suggests that CSCs are relatively resistant to conventional therapies and responsible for metastasis formation. Deciphering these processes will help understand oncogenesis and allow the development of new targeted therapies. Here, we have used a whole genome promoter microarray to establish the DNA methylation portraits of breast cancer stem cells (bCSCs) and non-bCSCs. A total of 68 differentially methylated regions (DMRs) were more hypomethylated in bCSCs than in non-bCSCs. Using a differentiation assay we demonstrated that DMRs are rapidly hypermethylated within the first 6 hours following induction of CSC differentiation whereas the cells reached the steady-state within 6 days, suggesting that these DMRs are linked to early CSC epigenetic regulation. These DMRs were significantly enriched in genes coding for TGF-b signaling-related proteins. Interestingly, DMRs hypomethylation was correlated to an overexpression of TGF-b signaling genes in a series of 109 breast tumors. Moreover, patients with tumors harboring the bCSC DMRs signature had a worse prognosis than those with nonbCSC DMRs signature. Our results show that bCSCs have a distinct DNA methylation landscape with TGF-b signaling as a key epigenetic regulator of bCSCs differentiation. STEM CELLS 2014;32:3031-3036

The role of hypoxia on the acquisition of epithelial-mesenchymal transition and cancer stemness: a possible link to epigenetic regulation

“…The increased expression of pluripotent genes coincides with their promoter demethylation, which suggests that demethylation of promoter DNA may be important in the epigenetic reprogramming of somatic cell nuclei [61]. Recently, El Helou et al [62] observed hypomethylation of breast CSCs in 68 differentially methylated regions compared with non-breast CSC populations, which worsen clinical outcomes.…”

DNA methylation and hydroxymethylation in stem cells

“…Moreover, promoter demethylation of achaete scute‐like 2 ( Ascl2 ), an essential transcription factor in maintaining ISC identity, results in the aberrant upregulation of ASCL2 in gastric cancer . In breast cancer stem cells (bCSCs), a whole‐genome promoter microarray analysis shows that 68 DMRs are more hypomethylated in bCSCs than in non‐bCSCs . These DMRs are significantly enriched in genes coding for transcription growth factor (TGF)‐β signalling‐related proteins, and interestingly, the hypomethylation of DMRs correlates to an overexpression of TGF‐β signalling genes in a series of 109 breast tumours, which implies that DNA methylation patterns affect tumour malignancy by regulating the transcription of genes relevant to bCSC multipotency and differentiation .…”

“…In breast cancer stem cells (bCSCs), a whole‐genome promoter microarray analysis shows that 68 DMRs are more hypomethylated in bCSCs than in non‐bCSCs . These DMRs are significantly enriched in genes coding for transcription growth factor (TGF)‐β signalling‐related proteins, and interestingly, the hypomethylation of DMRs correlates to an overexpression of TGF‐β signalling genes in a series of 109 breast tumours, which implies that DNA methylation patterns affect tumour malignancy by regulating the transcription of genes relevant to bCSC multipotency and differentiation . In a recent study, MSCs were reprogrammed to iPSCs and then redifferentiated into MSCs again .…”

“…163 These DMRs are significantly enriched in genes coding for transcription growth factor (TGF)-β signalling-related proteins, and interestingly, the hypomethylation of DMRs correlates to an overexpression of TGF-β signalling genes in a series of 109 breast tumours, which implies that DNA methylation patterns affect tumour malignancy by regulating the transcription of genes relevant to bCSC multipotency and differentiation. 163 In a recent study, MSCs were reprogrammed to iPSCs and then redifferentiated into MSCs again. 164 Although redifferentiated MSCs (from MSC-derived iPSCs) share the same morphology and gene expression profiles with primary MSCs, the DNA methylation patterns vary, with tissue-specific, senescence-associated and age-related DNA methylation patterns erased during reprogramming.…”

Targeting tumorigenicity of breast cancer stem-like cells using combination epigenetic therapy: something old and something new

“…A recent study used whole genome promoter microarray to compare the DNA methylation portraits of human BCSCs versus non-BCSCs, and showed a distinct DNA methylation landscape in BCSCs as a key epigenetic mediator of their differentiation (20). Epigenetic silencing of the tumor suppressor breast cancer 1 (BRCA1) gene due to CpG island hypermethylation in breast cancer which contained expanded luminal progenitor cells was reported in a recent study (21).…”