Abstract
Breast cancer has a high incidence and mortality rate worldwide. Several viral vectors including lentiviral, adenoviral and adeno-associated viral vectors have been used in gene therapy for various forms of human cancer, and have shown promising effects in controlling tumor development. Claudin1 (CLDN1) is a member of the tetraspan transmembrane protein family that plays a major role in tight junctions and is associated with tumor metastasis. However, the role of CLDN1 in breast cancer is largely unexplored. In this study, we tested the therapeutic potential of silencing CLDN1 expression in two breast cancer (MDA-MB-231 and MCF7) cell lines using lentiviral vector mediated RNA interference. We found that a CLDN1 short hairpin (shRNA) construct efficiently silenced CLDN1 expression in both breast cancer cell lines, and CLDN1 knockdown resulted in reduced cell proliferation, survival, migration and invasion. Furthermore, silencing CLDN1 inhibited epithelial to mesenchymal transition (EMT) by upregulating the epithelial cell marker, E-cadherin, and downregulating mesenchymal markers, smooth muscle cell alpha-actin (SMA) and Snai2. Our data demonstrated that lentiviral vector mediated CLDN1 RNA interference has great potential in breast cancer gene therapy by inhibiting EMT and controlling tumor cell growth.
Highlights
Breast cancer is the most common cancer in women and the leading cause of cancer death
To examine whether CLDN1 expression regulates epithelial to mesenchymal transition (EMT) in breast cancer cells, we examined the expression of the epithelial cell marker, E-cadherin, and the mesenchymal markers, Vimentin, Snai2 expression of the epithelial cell marker, E-cadherin, and the mesenchymal markers, Vimentin, Snai2 and and smooth muscle cell alpha-actin (SMA), in both MDA-MB-231 and MCF7 stable cells transduced with two different CLDN1
We have shown that CLDN1 was amplified and upregulated in the invasive breast carcinoma
Summary
Breast cancer is the most common cancer in women and the leading cause of cancer death. There are over 40,000 deaths reported annually in the US, the mortality rate is declining yearly [1]. A reason for the high mortality rate is inefficient chemotherapeutic drug delivery. Viral vectors, including adenoviral, adeno-associated, retroviral and lentiviral vectors, have high transduction efficiency in experimental animal models and have shown promise in clinical trials for treating a variety of human cancers [3,4,5,6,7,8]. Viral vector mediated RNA interference has been widely used to silence the expression of various target genes. Lentiviral vectors have been used widely for gene delivery including RNA interference. Lentiviral vectors have several important advantages over other viral vector systems in cancer therapy, including long term expression, high transduction efficiency, less antitumor immunity [11]. The most widely used lentiviral vector presently is a third generation vector modified by deleting viral promoter and separating viral structural genes into three packaging plasmids, which significantly reduces the possibility of generating replication competent viruses
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