Toronto General Research Institute - University Health Network, 67 College Street, Rm. 407, Toronto, Ontario, M5G 2M1, Canada.
Centre for Computational Biology, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Breast Cancer Res. 2019 Jan 31;21(1):18. doi: 10.1186/s13058-019-1098-z.
Triple-negative breast cancer (TNBC) represents a heterogeneous group of ER- and HER2-negative tumors with poor clinical outcome. We recently reported that Pten-loss cooperates with low expression of microRNA-145 to induce aggressive TNBC-like lesions in mice. To systematically identify microRNAs that cooperate with PTEN-loss to induce aggressive human BC, we screened for miRNAs whose expression correlated with PTEN mRNA levels and determined the prognostic power of each PTEN-miRNA pair alone and in combination with other miRs.
Publically available data sets with mRNA, microRNA, genomics, and clinical outcome were interrogated to identify miRs that correlate with PTEN expression and predict poor clinical outcome. Alterations in genomic landscape and signaling pathways were identified in most aggressive TNBC subgroups. Connectivity mapping was used to predict response to therapy.
In TNBC, PTEN loss cooperated with reduced expression of hsa-miR-4324, hsa-miR-125b, hsa-miR-381, hsa-miR-145, and has-miR136, all previously implicated in metastasis, to predict poor prognosis. A subgroup of TNBC patients with PTEN-low and reduced expression of four or five of these miRs exhibited the worst clinical outcome relative to other TNBCs (hazard ratio (HR) = 3.91; P < 0.0001), and this was validated on an independent cohort (HR = 4.42; P = 0.0003). The PTEN-low/miR-low subgroup showed distinct oncogenic alterations as well as TP53 mutation, high RB1-loss signature and high MYC, PI3K, and β-catenin signaling. This lethal subgroup almost completely overlapped with TNBC patients selected on the basis of Pten-low and RB1 signature loss or β-catenin signaling-high. Connectivity mapping predicted response to inhibitors of the PI3K pathway.
This analysis identified microRNAs that define a subclass of highly lethal TNBCs that should be prioritized for aggressive therapy.
三阴性乳腺癌（TNBC）代表一组异质性 ER 和 HER2 阴性肿瘤，临床预后较差。我们最近报道称，Pten 缺失与 microRNA-145 低表达协同作用，可在小鼠中诱导侵袭性 TNBC 样病变。为了系统地鉴定与 PTEN 缺失协同诱导侵袭性人 BC 的 microRNAs，我们筛选了与 PTEN mRNA 水平相关的 microRNAs，并单独和组合其他 microRNAs 确定了每个 PTEN-microRNA 对的预后能力。
利用公共 mRNA、microRNA、基因组学和临床结局数据集，鉴定与 PTEN 表达相关且预测不良临床结局的 microRNAs。在大多数侵袭性 TNBC 亚组中鉴定了基因组景观和信号通路的改变。连通性映射用于预测对治疗的反应。
在 TNBC 中，PTEN 缺失与 hsa-miR-4324、hsa-miR-125b、hsa-miR-381、hsa-miR-145 和 has-miR136 的表达降低协同作用，这些 microRNAs 均以前与转移有关，可预测不良预后。与其他 TNBC 相比，PTEN 低表达和这四种 microRNAs 中任意四种或五种 microRNAs 表达降低的 TNBC 患者亚组表现出最差的临床结局（风险比 (HR) = 3.91；P < 0.0001），并在独立队列中得到验证（HR = 4.42；P = 0.0003）。PTEN 低/miR 低亚组显示出明显的致癌改变，以及 TP53 突变、RB1 缺失标志物高、MYC、PI3K 和 β-catenin 信号高。这个致命的亚组几乎完全与基于 Pten 低和 RB1 缺失标志物或 β-catenin 信号高选择的 TNBC 患者重叠。连通性映射预测了对 PI3K 通路抑制剂的反应。
该分析鉴定了定义高度致命 TNBC 亚类的 microRNAs，应优先进行积极治疗。
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