Laboratorio Nazionale CIB, AREA Science Park, Trieste, Italy.
Cell Cycle. 2013 Jun 1;12(11):1679-87. doi: 10.4161/cc.24757. Epub 2013 May 1.
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.
乳腺癌是一种具有异质性的肿瘤类型，其特征是分子异常谱复杂，导致恶性特征和临床结果多样化。解析促进乳腺癌发展并作为侵袭性决定因素的分子机制是改善患者管理的首要需求。除其他改变外，在乳腺癌和其他人类肿瘤中发现了 microRNA 的异常表达，它们通过在转录后水平精细调节基因表达的能力，充当癌基因或肿瘤抑制因子。在这项研究中，我们描述了 miR-181a/b 作为乳腺癌中 DNA 损伤反应的负调节剂的新作用，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。我们报告说，miR-181a 和 miR-181b 在侵袭性更强的乳腺癌中过度表达，并且它们的表达与 ATM 水平呈负相关。此外，我们证明 miR-181a/b 的失调表达决定了三阴性乳腺癌细胞对聚 ADP-核糖聚合酶 1（PARP1）抑制的敏感性。这些证据表明，监测 miR-181a/b 的表达可能有助于根据 PARP1 抑制为乳腺癌和其他肿瘤类型量身定制更有效的治疗方法。
