MicroRNA 100 sensitizes luminal A breast cancer cells to paclitaxel treatment in part by targeting mTOR.
MicroRNA 100 sensitizes luminal A breast cancer cells to paclitaxel treatment in part by targeting mTOR.
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Micro RNA 100 部分通过靶向 mTOR 使 Luminal A 乳腺癌细胞对紫杉醇治疗敏感
DOI：
10.18632/oncotarget.6790
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发表时间：
2016-02-02
期刊：
影响因子：
--
通讯作者：
Dong JT
中科院分区：
文献类型：
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作者：
Zhang B;Zhao R;He Y;Fu X;Fu L;Zhu Z;Fu L;Dong JT
Luminal A型乳腺癌通常对激素治疗有反应，但不受益于化疗，包括微管靶向紫杉醇。microRNA可能在介导这种差异反应中发挥作用。在这项研究中，我们研究了microRNA 100（miR-100）在乳腺癌对紫杉醇治疗敏感性中的作用。我们发现，虽然miR-100在人乳腺癌原发性肿瘤和细胞系中下调，但在管腔A亚型中下调的程度大于其他亚型。紫杉醇在Luminal A中的IC 50远高于基底样乳腺癌细胞系。MCF-7 luminal A细胞系中的异位miR-100表达增强了紫杉醇对细胞周期停滞、多核化和凋亡的作用，而MDA-MB-231基底样细胞系中miR-100的敲低则损害了这些作用。类似地，miR-100的过表达增强了紫杉醇对MCF-7细胞中肿瘤发生的作用。雷帕霉素介导的哺乳动物雷帕霉素靶点（mTOR）（miR-100的靶点）的抑制也使MCF-7细胞对紫杉醇敏感。基因集富集分析显示，作为已知紫杉醇敏感特征的一部分的基因在乳腺癌样本中与miR-100具有显著的表达相关性。此外，miR-100表达水平较低的患者总体生存率较差。这些结果表明，miR-100在决定乳腺癌对紫杉醇治疗的敏感性方面起着因果作用。
Luminal A breast cancer usually responds to hormonal therapies but does not benefit from chemotherapies, including microtubule-targeted paclitaxel. MicroRNAs could play a role in mediating this differential response. In this study, we examined the role of micro RNA 100 (miR-100) in the sensitivity of breast cancer to paclitaxel treatment. We found that while miR-100 was downregulated in both human breast cancer primary tumors and cell lines, the degree of downregulation was greater in the luminal A subtype than in other subtypes. The IC50 of paclitaxel was much higher in luminal A than in basal-like breast cancer cell lines. Ectopic miR-100 expression in the MCF-7 luminal A cell line enhanced the effect of paclitaxel on cell cycle arrest, multinucleation, and apoptosis, while knockdown of miR-100 in the MDA-MB-231 basal-like line compromised these effects. Similarly, overexpression of miR-100 enhanced the effects of paclitaxel on tumorigenesis in MCF-7 cells. Rapamycin-mediated inhibition of the mammalian target of rapamycin (mTOR), a target of miR-100, also sensitized MCF-7 cells to paclitaxel. Gene set enrichment analysis showed that genes that are part of the known paclitaxel-sensitive signature had a significant expression correlation with miR-100 in breast cancer samples. In addition, patients with lower levels of miR-100 expression had worse overall survival. These results suggest that miR-100 plays a causal role in determining the sensitivity of breast cancers to paclitaxel treatment.