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首页> 外文期刊>Cell cycle >Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status.
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Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status.

机译：二甲双胍通过上皮-间质转化（EMT）状态的转录调控来调控乳腺癌干细胞的发生。

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The sole overexpression of pivotal regulators of the embryonic Epithelial-Mesenchymal Transition (EMT) genetic program ("EMT status") may be sufficient to efficiently drive the ontogeny of the breast cancer stem cell molecular signature independently of changes in EMT functioning ("EMT phenotype"). Using basal-like breast cancer models naturally enriched in either CD44(pos)CD24(loweg) or CD44(pos)CD24(pos) tumor-initiating cell populations we herein illustrate that non-cytotoxic concentrations of the anti-diabetic drug metformin efficiently impedes the ontogeny of generating the stem cell phenotype by transcriptionally repressing the stem cell property EMT. Metformin treatment dynamically regulated the CD44(pos)CD24(neg/low) breast cancer stem cell immunophenotype, transcriptionally reprogrammed cells through decreased expression of key drivers of the EMT machinery including the transcription factors ZEB1, TWIST1 and SNAI2 (Slug) and the pleiotrophic cytokines TGFbetas, and lastly impeded the propensity of breast cancer stem cells to form multicellular "microtumors" in non-adherent and non-differentiating conditions (i.e., "mammospheres"). These findings, altogether, provide strong motivation for the continued molecular understanding and clinical development of metformin as a non-toxic therapeutic aimed to interdict the breast cancer stem cell phenotype by targeting EMT, a molecular process that is central to the ontogenesis of the breast cancer stem cell molecular signature.
机译：胚胎上皮-间质转化（EMT）基因程序（“ EMT状态”）的关键调节因子的唯一过度表达可能足以有效地驱动乳腺癌干细胞分子标志的个体发育，而与EMT功能的改变无关（“ EMT表型” ”）。使用天然富集于CD44（pos）CD24（low / neg）或CD44（pos）CD24（pos）肿瘤启动细胞群的基底样乳腺癌模型，我们在此处说明了抗糖尿病药物二甲双胍的非细胞毒性浓度通过转录抑制干细胞特性EMT，有效地阻止了产生干细胞表型的存在。二甲双胍治疗可动态调节CD44（pos）CD24（neg / low）乳腺癌干细胞免疫表型，并通过减少EMT机制关键驱动因子（包括转录因子ZEB1，TWIST1和SNAI2（Slug）和多营养细胞因子）的表达来转录重编程细胞TGFbetas并最终阻碍了乳腺癌干细胞在非粘附和非分化条件下（即“乳腺球”）形成多细胞“微肿瘤”的倾向。这些发现总共为继续进行分子理解和二甲双胍作为一种无毒治疗药物的强大动力提供了动力，该药物旨在通过靶向EMT来阻断乳腺癌干细胞的表型，EMT是乳腺癌存在的关键分子过程。干细胞分子标记。

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