Tumor DNA hypomethylation of LINE-1 is associated with low tumor grade of breast cancer in Tunisian patients

International audienceDNA hypomethylation of long interspersed repetitive DNA retrotransposon (LINE‑1) and Alu repeats elements of short interspersed elements family (SINEs) is an early event in carcinogenesis that causes transcriptional activation and leads to chromosomal instability. In the current study, DNA methylation levels of LINE‑1 and Alu repeats were analyzed in tumoral tissues of invasive breast cancer in a Tunisian cohort and its association with the clinicopathological features of patients was defined. DNA methylation of LINE‑1 and Alu repeats were analyzed using pyrosequencing in 61 invasive breast cancers. Median values observed for DNA methylation of LINE‑1 and Alu repeats were considered as the cut‑off (59.81 and 18.49%, respectively). The results of the current study demonstrated a positive correlation between DNA methylation levels of LINE‑1 and Alu repeats (rho=0.284; P<0.03). DNA hypomethylation of LINE‑1 was also indicated to be associated with low grade (P=0.023). To the best of our knowledge, the current study is the first study regarding DNA methylation of LINE‑1 and Alu repeats element in breast cancer of the Tunisian population. The results of the current study suggest that, since hypomethylation of LINE‑1 is associated with low grade, it could be used as a biomarker for prognosis for patients with breast cancer

A genome-wide RNAi screen reveals essential therapeutic targets of breast cancer stem cells

International audienceTherapeutic resistance is a major clinical challenge in oncology. Evidence identifies cancer stem cells (CSCs) as a driver of tumor evolution. Accordingly, the key stemness property unique to CSCs may represent a reservoir of therapeutic target to improve cancer treatment. Here, we carried out a genome-wide RNA interference screen to identify genes that regulate breast CSCs-fate (bCSC). Using an interactome/regulome analysis, we integrated screen results in a functional mapping of the CSC-related processes. This network analysis uncovered potential therapeutic targets controlling bCSC-fate. We tested a panel of 15 compounds targeting these regulators. We showed that mifepristone, salinomycin, and JQ1 represent the best anti-bCSC activity. A combination assay revealed a synergistic interaction of salinomycin/JQ1 association to deplete the bCSC population. Treatment of primary breast cancer xenografts with this combination reduced the tumor-initiating cell population and limited metastatic development. The clinical relevance of our findings was reinforced by an association between the expression of the bCSC-related networks and patient prognosis. Targeting bCSCs with salinomycin/JQ1 combination provides the basis for a new therapeutic approach in the treatment of breast cancer