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首页> 外文期刊>Oncology reports >The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells.
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The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells.

机译：抗糖尿病药物二甲双胍可抑制MDA-MB-468三阴性乳腺癌细胞中的转移相关蛋白CD24。

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CD24, a mucin-like adhesion molecule that enhances the metastatic potential of malignant cells, has been suggested to be a marker of poor prognosis in breast carcinomas. The tumor-initiating potential of CD44posCD24pos cell populations has been recently recognized and, accordingly, distant metastases are largely composed of CD24-positive cells in breast cancer patients refractory to treatment. Therefore, new therapeutic strategies aimed at down-regulating CD24 may negatively regulate the dissemination of tumor cells and formation of metastasis. Here, we reveal that suppression of CD24 protein expression is a crucial event in the molecular mechanisms underlying the growth-inhibitory effects of the anti-diabetic drug metformin in MDA-MB-468 triple-negative (basal-like) breast cancer cells. First, we confirmed that, among the different molecular classes of breast cancer, basal-like breast cancer cells were significantly more sensitive to the growth-inhibitory effects of metformin. Second, we observed a positive correlation between the growth inhibitory activity of metformin and the relative enrichment in cells bearing the CD44posCD24pos immunophenotype. Third, high-content indirect immunofluorescence imaging assays revealed that CD24 protein levels were drastically decreased in the presence of growth-inhibitory concentrations of metformin. Fourth, to preliminary assess the clinical relevance of metformin's anti-CD24 effects we took advantage of the recently developed ROCK online interface (http://rock.icr.ac.uk/), a publicly accessible portal that allows rapid integration of breast cancer functional and molecular profiling datasets. When we evaluated the impact of CD24 expression on distant metastasis-free survival (DMFS) in microarray gene expression breast cancer datasets, Kaplan-Meier survival analyses and log-rank tests comparing DMSF for CD24-high and CD24-low breast carcinomas revealed that patients with CD24-high tumors tended to have a shorter DMFS. These findings, altogether, suggest that the ability of metformin to suppress the oncogene, metastasis promoter and breast cancer stem cell marker CD24 may open a novel molecular avenue in the therapeutic management of highly-metastastic subgroups of triple-negative (basal-like) breast cancers naturally enriched with CD44posCD24pos tumor-initiating cell populations.
机译：CD24是一种粘蛋白样黏附分子，可增强恶性细胞的转移潜能，已被认为是乳腺癌预后不良的标志。最近已经认识到CD44posCD24pos细胞群具有引发肿瘤的潜力，因此，在难以治疗的乳腺癌患者中，远处转移主要由CD24阳性细胞组成。因此，旨在下调CD24的新治疗策略可能会负调控肿瘤细胞的扩散和转移的形成。在这里，我们揭示了CD24蛋白表达的抑制是在MDA-MB-468三阴性（基底样）乳腺癌细胞中抗糖尿病药物二甲双胍的生长抑制作用的分子机制中的关键事件。首先，我们确认，在乳腺癌的不同分子类别中，基底样乳腺癌细胞对二甲双胍的生长抑制作用更为敏感。其次，我们观察到二甲双胍的生长抑制活性与带有CD44posCD24pos免疫表型的细胞的相对富集之间存在正相关。第三，高含量的间接免疫荧光成像分析表明，在存在抑制性二甲双胍浓度的情况下，CD24蛋白水平急剧下降。第四，为了初步评估二甲双胍抗CD24作用的临床相关性，我们利用了最近开发的ROCK在线界面（http://rock.icr.ac.uk/），该界面是可公开访问的门户网站，可以快速整合乳腺癌。功能和分子谱数据集。当我们评估CD24表达对微阵列基因表达乳腺癌数据集中的远处无转移生存（DMFS）的影响时，Kaplan-Meier生存分析和对数秩检验比较了DMSF对高CD24和低CD24乳腺癌的揭示，该患者CD24高的肿瘤患者的DMFS较短。这些发现总共表明，二甲双胍抑制癌基因，转移启动子和乳腺癌干细胞标志物CD24的能力可能为三阴性（基底样）乳腺癌的高转移亚组的治疗开辟新的分子途径。自然富含CD44posCD24pos肿瘤启动细胞群的癌症。

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