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Abstract：
Distant metastasis is a major cause of increased mortality in breast cancer patients, but the mechanisms underlying breast cancer metastasis remain poorly understood. In this study, we aimed to identify a metastasis-related gene (MRG) signature for predicting progression in breast cancer. By screening using three regression analysis methods, a 9-gene signature (NOTCH1, PTP4A3, MMP13, MACC1, EZR, NEDD9, PIK3CA, F2RL1 and CCR7) was constructed based on an MRG set in the BRCA cohort from TCGA. This signature exhibited strong robustness, and its generalizability was verified in the Metabric and GEO cohorts. Of the nine MRGs, EZR is an oncogenic gene with a well-documented role in cell adhesion and cell migration, but it has rarely been investigated in breast cancer. Based on a search of different databases, EZR was found to be significantly more highly expressed in both breast cancer cells and breast cancer tissue. EZR knockdown significantly inhibited cell proliferation, invasion, chemoresistance and EMT in breast cancer. Mechanistically, RhoA activation assays confirmed that EZR knockdown inhibited the activity of RhoA, Rac1 and Cdc42. In summary, we identified a nine-MRG signature that can be used as an efficient prognostic indicator for breast cancer patients, and owing to its involvement in regulating breast cancer metastasis, EZR might serve as a therapeutic target.
摘要：
远处转移是乳腺癌患者死亡率增加的主要原因，但对乳腺癌转移的潜在机制仍知之甚少。在这项研究中,我们旨在鉴定预测乳腺癌进展的转移相关基因(MRG)特征.通过使用三种回归分析方法进行筛选，9个基因签名(NOTCH1，PTP4A3，MMP13，MACC1，EZR，NEDD9,PIK3CA,F2RL1和CCR7）是基于来自TCGA的BRCA队列中的MRG集构建的。该签名表现出很强的鲁棒性，并在Metabric和GEO队列中验证了其普适性。在九个MRG中，EZR是一种致癌基因，在细胞粘附和细胞迁移中具有有据可查的作用，但它很少在乳腺癌中被研究。基于对不同数据库的搜索，发现EZR在乳腺癌细胞和乳腺癌组织中显著更高的表达。EZR敲低显著抑制细胞增殖，入侵,乳腺癌的化疗耐药和EMT。机械上,RhoA激活试验证实EZR敲低抑制RhoA的活性,Rac1和Cdc42。总之,我们确定了9-MRG特征，可以用作乳腺癌患者的有效预后指标，由于它参与调节乳腺癌转移，EZR可能作为治疗靶点。
