A Novel MAPK-microRNA Signature Is Predictive of Hormone-Therapy Resistance and Poor Outcome in ER-Positive Breast Cancer
A Novel MAPK-microRNA Signature Is Predictive of Hormone-Therapy Resistance and Poor Outcome in ER-Positive Breast Cancer
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DOI：
10.1158/1078-0432.ccr-14-2053
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发表时间：
2015-01-15
影响因子：
11.5
通讯作者：
El-Ashry, Dorraya
中科院分区：
文献类型：
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作者：
Miller, Philip C.;Clarke, Jennifer;El-Ashry, Dorraya
目的：ERK 1/2 MAPK（hMAPK）的过度激活导致乳腺癌雌激素受体（ER）表达缺失和预后不良。microRNA（miRNA）在疾病中起着重要的调控作用，是疾病的生物标志物。在这里，我们描述的hMAPK-miRNA表达签名在乳腺癌的分子，病理和临床结果associations实验设计：一个hMAPK-miRNA签名被确定，并确定在原发性乳腺癌从训练数据和使用独立的数据集验证的分子和遗传学改变，基因表达，病理特征和临床结果的关联。单变量和多变量分析确定了与ER阳性（ER+）patients.Results. High-hMAPK-miRNA状态显着相关的疾病复发率和较差的疾病生存率增加的子签名ER阴性，富集基础和HER 2亚型，并减少复发和疾病特异性生存在公开可用的数据集。对复发特征和存活特征的稳健测定鉴定了通常与不良临床结果相关的hMAPK-miRNA，以及与疾病复发或疾病存活更密切相关的特定子集，特别是在管腔A和管腔B亚型的ER+癌症中。多变量分析表明，这些复发和生存特征与ER+癌症和激素治疗的ER+癌症中疾病特异性死亡和疾病复发的风险增加显著相关。结论：我们报告了一个hMAPK-miRNA特征和两个来自它的子特征，它们与乳腺癌的不良临床特征、不良临床结局和对激素治疗的不良反应显著相关，从而鉴定了MAPK信号的潜在效应子，以及乳腺癌的新的预测和预后生物标志物或治疗靶点。21（2）; 373-85.©2014 AACR.
Purpose:Hyperactivation of ERK1/2 MAPK (hMAPK) leads to loss of estrogen receptor (ER) expression and poor outcome in breast cancer. microRNAs (miRNA) play important regulatory roles and serve as biomarkers of disease. Here, we describe molecular, pathologic, and clinical outcome associations of an hMAPK–miRNA expression signature in breast cancer.Experimental Design:An hMAPK–miRNA signature was identified, and associations of this signature with molecular and genetic alterations, gene expression, pathologic features, and clinical outcomes were determined in primary breast cancers from training data and validated using independent datasets. Univariate and multivariate analyses identified subsignatures associated with increased disease recurrence and poorer disease survival among ER-positive (ER+) patients, respectively.Results:High-hMAPK–miRNA status significantly correlated with ER-negativity, enrichment for basal and HER2-subtypes, and reduced recurrence-free and disease-specific survival in publicly available datasets. A robust determination of a recurrence signature and a survival signature identified hMAPK–miRNAs commonly associated with poor clinical outcome, and specific subsets associated more closely with either disease recurrence or disease survival, especially among ER+cancers of both luminal A and luminal B subtypes. Multivariate analyses indicated that these recurrence and survival signatures significantly associated with increased risk of disease-specific death and disease recurrence in ER+cancer and ER+cancers treated with hormone therapy.Conclusions:We report an hMAPK–miRNA signature and two subsignatures derived from it that associate significantly with adverse clinical features, poor clinical outcome, and poor response to hormone therapy in breast cancer, thus identifying potential effectors of MAPK signaling, and novel predictive and prognostic biomarkers or therapeutic targets in breast cancer.Clin Cancer Res; 21(2); 373–85. ©2014 AACR.