EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy
EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy
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DOI：
10.1158/0008-5472.can-04-0754
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发表时间：
2004-08-15
期刊：
影响因子：
11.2
通讯作者：
Gillanders, WK
中科院分区：
文献类型：
--
作者：
Osta, WA;Chen, Y;Gillanders, WK
EpCAM（上皮细胞粘附分子）是已知在结肠和其它上皮癌中高度表达的细胞表面分子。EpCAM参与细胞与细胞的粘附，在几项临床试验中已成为抗体治疗的靶点。为了评估EpCAM作为乳腺癌基因治疗的新靶点的价值，我们进行了实时逆转录PCR，以定量正常乳腺组织和原发性和转移性乳腺癌中EpCAM mRNA的表达水平。我们发现EpCAM在原发性和转移性乳腺癌中过表达100至1000倍。用EpCAM短干扰RNA（siRNA）沉默EpCAM基因表达导致四种不同乳腺癌细胞系的细胞增殖速率降低35-80%。EpCAM siRNA处理在体外使乳腺癌细胞系MDA-MB-231中的细胞迁移降低91.8%，细胞侵袭降低96.4%。EpCAM siRNA处理还与E-钙粘蛋白、α-连环蛋白和β-连环蛋白的洗涤剂不溶性蛋白质部分的增加相关，这与EpCAM作为细胞粘附调节剂的已知生物学一致。我们的假设是EpCAM表达的调节可以通过增强E-钙粘蛋白介导的细胞间粘附来影响细胞迁移、侵袭和增殖。这些数据提供了令人信服的证据，EpCAM是乳腺癌基因治疗的潜在新靶点，并提供了与EpCAM基因沉默相关的机制的见解。
EpCAM (epithelial cell adhesion molecule) is a cell surface molecule that is known to be highly expressed in colon and other epithelial carcinomas. EpCAM is involved in cell-to-cell adhesion and has been the target of antibody therapy in several clinical trials. To assess the value of EpCAM as a novel target for breast cancer gene therapy, we performed real-time reverse transcription-PCR to quantify the level of EpCAM mRNA expression in normal breast tissue and primary and metastatic breast cancers. We found that EpCAM is overexpressed 100- to 1000-fold in primary and metastatic breast cancer. Silencing EpCAM gene expression with EpCAM short interfering RNA (siRNA) resulted in a 35-80% decrease in the rate of cell proliferation in four different breast cancer cell lines. EpCAM siRNA treatment decreased cell migration by 91.8% and cell invasion by 96.4% in the breast cancer cell line MDA-MB-231 in vitro. EpCAM siRNA treatment was also associated with an increase in the detergent-insoluble protein fraction of E-cadherin, alpha-catenin, and beta-catenin, consistent with the known biology of EpCAM as a regulator of cell adhesion. Our hypothesis is that modulation of EpCAM expression can affect cell migration, invasion, and proliferation by enhancing E-cadherin-mediated cell-to-cell adhesion. These data provide compelling evidence that EpCAM is a potential novel target for breast cancer gene therapy and offer insights into the mechanisms associated with EpCAM gene silencing.