Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer.
Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-15-2711
复制
发表时间：
2016-12-01
期刊：
影响因子：
--
通讯作者：
Feng FY
中科院分区：
文献类型：
--
作者：
Speers C;Zhao SG;Kothari V;Santola A;Liu M;Wilder-Romans K;Evans J;Batra N;Bartelink H;Hayes DF;Lawrence TS;Brown PH;Pierce LJ;Feng FY
虽然雌激素受体阳性和HER 2阳性乳腺癌存在有效的靶向疗法，但三阴性乳腺癌（TNBC）不存在这样的有效疗法;因此，显然迫切需要用于放射增敏和治疗的其他靶点。使用表达微阵列、qRT-PCR和蛋白质印迹来评估MELK RNA和蛋白质表达水平。克隆形成存活测定用于定量基线和MELK抑制后细胞系的放射敏感性。使用γ H2 AX染色确定MELK敲低对DNA损伤修复动力学的影响。使用小鼠异种移植模型进行MELK敲低对放射敏感性的体内影响。Kaplan-Meier分析用于估计局部控制和生存信息，并构建考克斯比例风险模型以识别影响局部无复发生存的潜在因素。与正常组织相比，MELK表达在乳腺癌组织中显著升高，以及与非TNBC相比，MELK表达在TNBC中显著升高。MELK RNA和蛋白表达与乳腺癌细胞系的放射抗性显著相关。抑制MELK（遗传和非遗传）在体外诱导辐射敏感性，并在多种模型中显著延迟体内肿瘤生长。Kaplan-Meier生存和多变量分析确定MELK表达增加是多个独立数据集中放射抗性和局部复发增加的最强预测因子。在这里，我们将MELK确定为TNBC中放射抗性的潜在生物标志物和放射增敏的靶点。我们的结果支持开发临床策略以抑制MELK作为TNBC中的新靶点的基本原理。
While effective targeted therapies exist for estrogen receptor–positive and HER2-positive breast cancer, no such effective therapies exist for triple-negative breast cancer (TNBC); thus, it is clear that additional targets for radiosensitization and treatment are critically needed. Expression microarrays, qRT-PCR, and Western blotting were used to assess MELK RNA and protein expression levels. Clonogenic survival assays were used to quantitate the radiosensitivity of cell lines at baseline and after MELK inhibition. The effect of MELK knockdown on DNA damage repair kinetics was determined using γH2AX staining. The in vivo effect of MELK knockdown on radiosensitivity was performed using mouse xenograft models. Kaplan–Meier analysis was used to estimate local control and survival information, and a Cox proportional hazards model was constructed to identify potential factors impacting local recurrence-free survival. MELK expression is significantly elevated in breast cancer tissues compared with normal tissue as well as in TNBC compared with non-TNBC. MELK RNA and protein expression is significantly correlated with radioresistance in breast cancer cell lines. Inhibition of MELK (genetically and pharmacologically) induces radiation sensitivity in vitro and significantly delayed tumor growth in vivo in multiple models. Kaplan–Meier survival and multivariable analyses identify increasing MELK expression as being the strongest predictor of radioresistance and increased local recurrence in multiple independent datasets. Here, we identify MELK as a potential biomarker of radioresistance and target for radiosensitization in TNBC. Our results support the rationale for developing clinical strategies to inhibit MELK as a novel target in TNBC.