Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer.
Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer.
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DOI：
10.4161/cc.24757
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发表时间：
2013-06-01
期刊：
影响因子：
--
通讯作者：
Del Sal G
中科院分区：
文献类型：
--
作者：
Bisso A;Faleschini M;Zampa F;Capaci V;De Santa J;Santarpia L;Piazza S;Cappelletti V;Daidone M;Agami R;Del Sal G
乳腺癌是一种异质性肿瘤类型，其特征在于复杂的分子畸变谱，导致多种恶性特征和临床结局。破译的分子机制，燃料乳腺癌的发展，并作为侵略性的决定因素是一个主要需要改善患者的管理。在其他改变中，已经在乳腺癌和其他人类肿瘤中发现了microRNA的异常表达，其中它们凭借其在转录后水平精细调节基因表达的能力而充当癌基因或肿瘤抑制因子。在这项研究中，我们描述了miR-181 a/B作为乳腺癌DNA损伤反应负调节因子的新作用，影响应激传感器激酶共济失调毛细血管扩张突变（ATM）的表达和活性。我们报道了miR-181 a和miR-181 b在更侵袭性的乳腺癌中过表达，它们的表达与ATM水平呈负相关。此外，我们证明了miR-181 a/B的表达失调决定了三阴性乳腺癌细胞对聚ADP-核糖聚合酶1（PARP 1）抑制的敏感性。这些证据表明，监测miR-181 a/B的表达可能有助于在乳腺癌和其他肿瘤类型中基于抑制PARP 1来定制更有效的治疗。
Breast cancer is a heterogeneous tumor type characterized by a complex spectrum of molecular aberrations, resulting in a diverse array of malignant features and clinical outcomes. Deciphering the molecular mechanisms that fuel breast cancer development and act as determinants of aggressiveness is a primary need to improve patient management. Among other alterations, aberrant expression of microRNAs has been found in breast cancer and other human tumors, where they act as either oncogenes or tumor suppressors by virtue of their ability to finely modulate gene expression at the post-transcriptional level. In this study, we describe a new role for miR-181a/b as negative regulators of the DNA damage response in breast cancer, impacting on the expression and activity of the stress-sensor kinase ataxia telangiectasia mutated (ATM). We report that miR-181a and miR-181b were overexpressed in more aggressive breast cancers, and their expression correlates inversely with ATM levels. Moreover we demonstrate that deregulated expression of miR-181a/b determines the sensitivity of triple-negative breast cancer cells to the poly-ADP-ribose-polymerase1 (PARP1) inhibition. These evidences suggest that monitoring the expression of miR-181a/b could be helpful in tailoring more effective treatments based on inhibition of PARP1 in breast and other tumor types.
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影响因子：
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