Abstract 3881: A distinct DNA methylation signature defines breast cancer stem cells and predict cancer outcome

Abstract

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

Biophysical and Epigenetic Regulation of Cancer Stemness, Invasiveness, and Immune Action

“…Hypomethylation of differentially methylated regions (DMRs) enriched in genes encoding proteins involved in TGF-β signaling leads to overexpression of the TGF-β signaling pathway in breast CSCs [200].…”