Quantifying Argonaute 2 (Ago2) expression to stratify breast cancer
Quantifying Argonaute 2 (Ago2) expression to stratify breast cancer
复制标题
DOI：
10.1186/s12885-019-5884-x
复制
发表时间：
2019-07-19
期刊：
影响因子：
3.8
通讯作者：
Brown, J. A.
中科院分区：
文献类型：
--
作者：
Casey, M. C.;Prakash, A.;Brown, J. A.
背景：精氨酸转运蛋白-2(Ago2)是微小RNA生物发生的重要组成部分，与肿瘤发生密切相关。然而，Ago2在乳腺癌中的表达和定位仍未确定。目的：明确Ago2在乳腺癌中的表达和定位，并探讨其与临床病理特征的关系。方法：对乳腺癌细胞系和组织芯片(TMA)中AGO2蛋白进行染色，并对染色强度和定位进行评估。染色强度与临床病理细节相关。结果：在乳腺癌组织中，有4种不同的染色强度(阴性、弱、中、强)，其中64.2%的标本Ago2蛋白表达弱或阴性。Ago2的强染色与Her2阳性或基本亚型，以及Ago2强度与受体状态(雌激素或孕激素)之间存在关联。在肿瘤中，Ago2mRNA的表达与无复发生存率的降低有关。相反，在SK-BR-3(HER2阳性)和BT-20(基础/三重阴性)细胞系中，Ago2mRNA的表达显著降低。有趣的是，在多个患者数据集中，乳腺癌患者中观察到高水平的Ago2基因扩增(10-27%)。重要的是，了解Ago2的表达可将乳腺癌亚型的预测提高20%，ER状态提高15.7%，PR状态提高17.5%。结论：Ago2的量化改善了乳腺癌的分层，并提示Ago2在乳腺癌亚型中的不同作用，基于水平和细胞定位。进一步研究影响Ago2失调的机制将揭示支持乳腺癌亚型的分子差异。
Background: Argonaute-2 (Ago2) is an essential component of microRNA biogenesis implicated in tumourigenesis. However Ago2 expression and localisation in breast cancer remains undetermined. The aim was to define Ago2 expression (mRNA and protein) and localisation in breast cancer, and investigate associations with clinicopathological details.Methods: Ago2 protein was stained in breast cancer cell lines and tissue microarrays (TMAs), with intensity and localization assessed. Staining intensity was correlated with clinicopathological details. Using independent databases, Ago2 mRNA expression and gene alterations in breast cancer were investigated.Results: In the breast cancer TMAs, 4 distinct staining intensities were observed (Negative, Weak, Moderate, Strong), with 64.2% of samples stained weak or negatively for Ago2 protein. An association was found between strong Ago2 staining and, the Her2 positive or basal subtypes, and between Ago2 intensity and receptor status (Estrogen or Progesterone). In tumours Ago2 mRNA expression correlated with reduced relapse free survival. Conversely, Ago2 mRNA was expressed significantly lower in SK-BR-3 (HER2 positive) and BT-20 (Basal/Triple negative) cell lines. Interestingly, high levels of Ago2 gene amplification (10-27%) were observed in breast cancer across multiple patient datasets. Importantly, knowledge of Ago2 expression improves predictions of breast cancer subtype by 20%, ER status by 15.7% and PR status by 17.5%.Conclusions: Quantification of Ago2 improves the stratification of breast cancer and suggests a differential role for Ago2 in breast cancer subtypes, based on levels and cellular localisation. Further investigation of the mechanisms affecting Ago2 dysregulation will reveal insights into the molecular differences underpinning breast cancer subtypes.