Breast cancer stem cells (bCSCs) have been implicated in tumor progression and therapeutic resistance; however, the molecular mechanisms that define this state are unclear. We have performed two microRNA (miRNA) gain- and loss-of-function screens to identify miRNAs that regulate the choice between bCSC self-renewal and differentiation. We find that micro-RNA (miR)-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal, leading to decreased in vivo tumorigenicity. miR-600 targets stearoyl desaturase 1 (SCD1), an enzyme required to produce active, lipid-modified WNT proteins. In the absence of miR-600, WNT signaling is active and promotes self-renewal, whereas overexpression of miR-600 inhibits the production of active WNT and promotes bCSC differentiation. In a series of 120 breast tumors, we found that a low level of miR-600 is correlated with active WNT signaling and a poor prognosis. These findings highlight a miR-600-centered signaling network that governs bCSC-fate decisions and influences tumor progression.
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
Pluripotency of stem cells depends on epigenetic programs that regulate self-renewal and differentiation. During oncogenesis, 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 gain insight into oncogenesis and allow the development of new targeted therapies. We used a whole-genomic promoter microarray to establish the DNA methylation portrait of breast cancer stem cells (bCSC) and compared it to non-bCSC. bCSC from five breast cancer cell lines were isolated using the ALDEFLUOR assay. We identified a DNA methylation signature with 68 differentially methylated regions (DMRs) that were hypomethylated in bCSCs as compared to non-bCSCs. Using a differentiation assay we demonstrated that DMRs are rapidly hypermethylated within the first six 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. DMRs were enriched in genes coding for TGFβ signaling-related proteins. Interestingly, overexpression of TGFβ signaling genes was correlated to DMRs hypomethylation in a series of 109 breast tumors. Moreover, the tumors harboring the bCSC DMRs signature had a worse evolution than the ones with the non-bCSC DMRs signature. Our results provide evidence that bCSCs harbor a distinct DNA methylation landscape with TGFβ signaling as a key epigenetic regulator of bCSCs differentiation. Note: This abstract was not presented at the meeting. Citation Format: Rita El Helou, Julien Wicinski, Arnaud Guille, Jose Adelaide, Pascal Finetti, Francois Bertucci, Max Chaffanet, Daniel Birnbaum, Emmanuelle Charafe-Jauffret, Christophe Ginestier. A distinct DNA methylation signature defines breast cancer stem cells and predict cancer outcome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3881. doi:10.1158/1538-7445.AM2014-3881
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