Protein kinase Cε is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy
Protein kinase Cε is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy
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DOI：
10.1158/0008-5472.can-05-0553
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发表时间：
2005-09-15
期刊：
影响因子：
11.2
通讯作者：
Merajver, SD
中科院分区：
文献类型：
--
作者：
Pan, Q;Bao, LW;Merajver, SD
肿瘤转移是乳腺癌患者发病和死亡的主要原因。识别促使转移的基因并了解它们如何导致转移表型的特定方面，对于改善临床检测和治疗至关重要。蛋白激酶C ε（PKC ε）是丝氨酸/苏氨酸蛋白激酶家族的一员，是一种转化癌基因，据报道与细胞侵袭和运动有关。在这项研究中，我们探讨了PKC ε在乳腺癌发生和发展中的作用。高密度组织微阵列分析显示，在浸润性导管乳腺癌患者的73.6%（144例中的106例）原发性肿瘤中检测到PKC ε蛋白。PKC ε染色强度增加与组织学分级高（P = 0.0206）、Her2/neu受体阳性（P = 0.0419）以及雌激素（P = 0.0026）和孕激素受体阴性（P = 0.0008）相关。Kaplan - Meier分析表明，PKC ε与较差的无病生存期和总生存期显著相关（对数秩检验，P = 0.0478和P = 0.0414）。在MDA - MB231细胞（一种PKC ε水平升高的侵袭性乳腺癌细胞系）中对PKC ε进行RNA干扰，导致细胞表型的增殖、侵袭和运动能力明显低于亲本细胞或对照RNA干扰转染细胞。此外，小干扰RNA - PKC ε MDA - MB231克隆在体内的肿瘤生长显著减缓了87%（P < 0.05），肺转移发生率抑制了83%（P < 0.02）。发现PKC ε缺陷克隆的RhoC GTP酶蛋白水平和活化程度较低。综上所述，这些结果表明PKC ε在促进侵袭性转移性乳腺癌表型方面起着关键的致病作用，是抗癌治疗的一个靶点。
Tumor metastasis is the major cause of morbidity and mortality in patients with breast cancer. It is critical to identify metastasis enabling genes and understand how they are responsible for inducing specific aspects of the metastatic phenotype to allow for improved clinical detection and management. Protein kinase C epsilon (PKC epsilon), a member of a family of serine/threonine protein kinases, is a transforming oncogene that has been reported to be involved in cell invasion and motility. In this study, we investigated the role of PKC epsilon in breast cancer development and progression. High-density tissue microarray analysis showed that PKC epsilon protein was detected in 73.6% (106 of 144) of primary tumors from invasive ductal breast cancer patients. Increasing PKCe staining intensity was associated with high histologic grade (P = 0.0206), positive Her2/neu receptor status (P = 0.0419), and negative estrogen (P = 0.0026) and progesterone receptor status (P = 0.0008). Kaplan-Meier analyses showed that PKC epsilon was significantly associated with poorer disease-free and overall survival (log-rank, P = 0.0478 and P = 0.0414, respectively). RNA interference of PKCe in MDA-MB231 cells, an aggressive breast cancer cell line with elevated PKC epsilon levels, resulted in a cell phenotype that was significantly less proliferative, invasive, and motile than the parental or the control RNA interference transfectants. Moreover, in vivo tumor growth of small interfering RNA-PKC epsilon MDA-MB231 clones was retarded by a striking 87% (P < 0.05) and incidence of lung metastases was inhibited by 83% (P < 0.02). PKC epsilon-deficient clones were found to have lower RhoC GTPase protein levels and activation. Taken together, these results revealed that PKC epsilon plays a critical and causative role in promoting an aggressive metastatic breast cancer phenotype and as a target for anticancer therapy.