Pan Quintin, Bao Li Wei, Kleer Celina G, Sabel Michael S, Griffith Kent A, Teknos Theodoros N, Merajver Sofia D
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Health System, Ann Arbor, Michigan 48109, USA.
Cancer Res. 2005 Sep 15;65(18):8366-71. doi: 10.1158/0008-5472.CAN-05-0553.
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 PKC epsilon 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 PKC epsilon 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.
肿瘤转移是乳腺癌患者发病和死亡的主要原因。识别促进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Cε（PKCε）是丝氨酸/苏氨酸蛋白激酶家族的成员，是一种转化癌基因，据报道参与细胞侵袭和运动。在本研究中，我们调查了PKCε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PKCε蛋白。PKCε染色强度增加与高组织学分级（P = 0.0206）、Her2/neu受体阳性状态（P = 0.0419）以及雌激素阴性（P = 0.0026）和孕激素受体阴性状态（P = 0.0008）相关。Kaplan-Meier分析表明，PKCε与无病生存期和总生存期较差显著相关（对数秩检验，分别为P = 0.0478和P = 0.0414）。在PKCε水平升高的侵袭性乳腺癌细胞系MDA-MB231细胞中，对PKCε进行RNA干扰，导致细胞表型与亲本或对照RNA干扰转染细胞相比，增殖、侵袭和运动能力显著降低。此外，小干扰RNA-PKCε MDA-MB231克隆的体内肿瘤生长显著减缓87%（P < 0.05），肺转移发生率降低83%（P < 0.02）。发现PKCε缺陷克隆的RhoC GTPase蛋白水平和活性较低。综上所述，这些结果表明PKCε在促进侵袭性转移性乳腺癌表型中起关键和因果作用，可作为抗癌治疗的靶点。
