EpCAM Is Overexpressed in Breast Cancer and Is a Potential Target for Breast Cancer Gene Therapy

Abstract

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, ␣-catenin, and ␤-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-cadherinmediated 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.

EpCAM (CD326) finding its role in cancer

“…As reviewed by W Gillanders (St Louis, USA), EpCAM overexpression on breast cancer cell lines is mandatory for proliferation, migration, and invasiveness of tumour cells (Osta et al, 2004). Knockdown of EpCAM expression by specific short interfering RNA had profound effects on the expression of certain genes.…”

“…In 2004, first evidence for a direct role of EpCAM in growth-promoting nuclear signalling was reported (Munz et al, 2004). These data and results published by the group of Gillanders (Osta et al, 2004) revived research on the biological function of EpCAM, which is now delivering breakthrough results.…”

“…This name is proposed to be EpCAM (without a dash) as an abbreviation for the ability of the protein to act as an epithelial-specific cell adhesion molecule (Litvinov et al, 1994) and activating molecule (Munz et al, 2004;Osta et al, 2004). It is also suggested to add in brackets on the first occurrence of the EpCAM name in a text the recently introduced cellular differentiation (CD) marker nomenclature for EpCAM, namely CD326.…”

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

“…Thirdly, EpCAM is expressed on socalled cancer stem cells in breast cancer and only those stem cells expressing EpCAM are highly tumorigenic in immunodeficient mice [52]. Fourthly, knockdown of Ep-CAM expression by a specific small inhibitory RNA in breast cancer cell lines inhibited proliferation, migration and invasiveness of cancer cells [53], and overexpression of EpCAM in quiescent cells increased these oncogenic parameters [54]. Based on the present data and the emerging biology of EpCAM in breast cancer, MT110 appears as an attractive therapeutic option for treatment of metastatic and therapeutic resistant stages of the disease.…”

Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers

“…Epithelial cell adhesion molecule was then found to be expressed at a high level and frequency not only on colon cancer tissues but on most human adenocarcinomas as well as on squamous cell carcinomas (Quak et al, 1990). In the case of breast and ovarian cancers, Ep-CAM mRNA was found to be more than 100-fold overexpressed relative to normal epithelial tissues (Kim et al, 2003;Osta et al, 2004).…”