A protein primarily active in developing embryos but silenced in normal adult tissues was found to be highly expressed in certain types of human breast cancer and could be a possible target for breast cancer treatment. Breast cancer patients regularly express a protein called receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) (Zhang et al. 2012). Normal cells and tissues in adults do not express ROR1. This protein is highly expressed during embryogenesis in order to synchronize heart, lungs and skeletal development. However, the expression of this protein is switched off at some fetal development phase.
Scientists have examined the effect of blocking ROR1 expression in human breast cancer cells. They found out the growth and survival of tumor cells had been impaired in vitro and also in animal xenograft model after silencing the expression of ROR1 (Zhang et al. 2012). That suggests ROR1 could be a good target for treating the most aggressive kinds of breast cancer, particularly the ones that lack expression of hormone receptors or over-expression of HER2 oncogene (human epidermal growth factor receptor type 2). RNA interference (RNAi) technologies that can target receptor tyrosine kinases and subsequently inhibit breast cancer progression in humans through demonstration of binding to associated mRNA to prevent the production of specific proteins in various breast cancers are proposed.
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This literature review will emphasize on the role of ROR1 in promoting the aggressiveness of breast cancers, notably HER2 that are over-expressed in that tumor. Further understanding on the mechanisms of targeting associated growth factor receptors and clinical trials could, in the future, allow the development of therapeutic agents and vaccines to against breast cancer.
The association of ROR1 with breast cancer cells
Expression of ROR1 encourages persistence and growth of tumor cells. Scientists have characterized some molecular pathways linked to preclusion of the growth of breast cancer cells by regulating ROR1. The research of Yang and Stockwell (2008) showed ROR1 interacted with casein kinase 1 epsilon (CK1É›) found in breast cancer to trigger phosphoinositide 3-kinase-mediated AKT phosphorylation and cAMP-response-element-binding protein (CREB). However, Trantirkova et al. (2010) investigated further and found that the mutations of CK1É› gene will restrain Wnt/Î²-catenin pathway as well as promote Wnt/Rac-1/JNK and Wnt/NFAT pathways. This is likely to enhance the breast tumor growth via effects on cell adhesion and cell migration or epithelial-mesenchymal transition (EMT) (Trantirkova et al. 2010).
It was also demonstrated that the EMT expression cause poor diagnosis in primary breast cancers or in patients with tumors over-expressing an EMT inducer, which is CD146 (Zeng et al. 2011). Nevertheless, the experiments demonstrated by Jiang et al. (2012) successfully identified several anti CD146 signals, such as the anti-CD146 (AA98) and anti-VEGF that play an stabilizer inhibitory effect on tumor-related angiogenesis. The recent studies by Zhang et al. (2012) also demonstrated that when ROR1 was suppressed, it shrinks the capacity of the cancer cells to survive in the presence of anticancer agents or generate tumors altogether. Mikels & Nusse (2006) suggested that Wnt5a, a ligand of ROR1, can be suppressed to block ROR1-dependent signaling and hence, inhibit tumor cell growth. Pharmaceutical agents that can block this ROR1-dependent signaling pathways are being tested and still under development.
RNAi or small molecule components could be developed as cancer prognostics to regulate the function of Wnt or CD146 signaling pathways (Madhusudan & Ganesan 2004). One of the approaches to target protein tyrosine kinases is using small interfering RNA (siRNA) to silence the ROR1 genes over-expressed in cancer cells, hence slow down breast cancer growth. The RNAi pathway consists of dicer, which makes small RNA duplexes (about 22 nucleotides) from double-stranded RNA (Yang and Stockwell 2008). One small RNA duplex strand is integrated into an effector complex known as RNAi-induced silencing complex (RISC). Depends on the extent of base-pair counterpart with the target mRNA, siRNA can acts as a guide molecule by guiding the RISC complex in translational suppression or mRNA cleavage (Thomson et al. 2011).
The role of HER2 in the breast cancer progression
HER2 proto-oncogene (also known as neu or c-erbB-2) plays a central role in normal breast growth and development (Yarden 2001). Over-expression of the HER2 genes is linked with metastatic breast cancer. According to the research by Slamon et al. (2001), the amplification of HER2 gene had been seen in approximately 30% of breast cancers which lead to extraordinarily high levels of encoded proteins produced in malignant tumor cells. Cobleigh et al. (1999) had studied that 185-kd transmembrane glycoprotein receptor (p185HER2) encoded by HER2 gene can be targeted by monoclonal antibodies, which can directly inhibit the growth of HER2-overexpressing tumor cells.
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Recent studies by Menendez et al. (2004) on ovarian cancer model indicated that pharmacological fatty acid synthase (FAS) inhibitors such as cerulenin and C75 could suppress p185HER2 expression and enzyme (tyrosine kinase activity) in breast. Pizer et al. (1998) had previously noted that cerulenin and C75 are selectively cytotoxic by inducing apoptosis to human cancer cells. Similar experiment was conducted by Huang et al. (2000) to study the effects of FAS inhibitor on cell growth by observing cell death through DNA fragmentation assay using agarose gel electrophoresis. Menendez et al. (2004) had concluded that p185HER2 oncoprotein expression was significantly down-regulated at the transcriptional level when using RNAi highly sequence-specific mechanism to silence FAS gene expression.
Researchers had found an innovative technique to block the translation of mRNA transcripts into protein that promote tumor growth by utilizing siRNA technology to silence the biochemical signals that attract a specific group of proteins to regions of tumor growth. The siRNA mediated knock-down of HER2 genes silencing in tumor cells causes a decrease in cancer cell proliferation (Yang & Stockwell 2008). In order to confirm the hypothesis of knocking down HER2 expression is accountable for the tumor growth inhibition, multiple dsRNA clones was used to target the HER2 gene. If more than a single dsRNA clone induces growth inhibition, HER2 is likely to be the relevant target, as the probability of a common off-target effect of multiple dsRNA clones with unrelated sequences is low.
RNAi is an effective approach for reducing or silencing expression of endogenously expressed proteins by means to suppress metastatic breast tumor formation. There are two types of RNA molecules - micro RNA (miRNA) and small interfering RNA (siRNA) involves in the RNAi mechanism through binding to mRNA molecules. The advantages of siRNA over miRNAs include specificity and effectiveness against invading viruses and transposons and can be designed against nearly any gene (Li et al. 2006). While miRNAs have incomplete base pairing to a target and inhibit the translation of many different mRNAs with similar sequences, however, siRNAs have perfect complementarity and induce mRNA decay only in a single, specific target (Li et al. 2006). In addition, some siRNAs have the ability to silence other genes besides complementary target genes but miRNAs will lose the gene silencing ability.
The siRNA-based therapies that can target tumor cells to suppress the production of proteins essential for the growth of breast cancer cells is a promising strategy in the cancer field. However, the biggest challenge in the use of siRNA machinery is the difficulty of delivery. The current available vectors used for delivery of siRNA are viral or bacterial vector and non-viral vector. Naked RNAs cannot break through the lipid membranes of a cell and thus, systemic application of unmodified viral or bacterial vectors is improbable to drive the siRNAs towards the desired target cell (Li et al. 2006).
A recent finding shows that nanoparticle-based system had been developed for delivering siRNA molecules to the correct cellular location (Zhang et al. 2012). Nanoparticles are designed to deliver and specifically localize siRNA in desired cells and tissues, at the same time minimize side effects and decreases the concentrations of siRNA required for efficient gene silencing in vivo. Nanoparticle-based technique can target specific receptors but on the other hand, it requires technical expertise and extreme precision in developing the right siRNA molecules. Scientists had demonstrated the efficacy of siRNA silencing using cDNA microarrays in mice model (Kononen et al. 1998).
Figure 1. Mechanism of siRNA pathways in mammals. Long double-stranded RNA (dsRNA) molecules (500-1000 nucleotides) are processed by Dicer enzyme into short (about 20-24-mer) small interfering RNA (siRNA) fragments with 3'dinucleotide overhangs. In the pre-RISC complex, an Argonautes (Ago) protein cleaves the passenger strand and liberates the guide strand in the mature RISC. Then, the activated RISC is able to cleave the target mRNAs.
(Davidson & McCray 2011)
Despite innovations in the diagnosis and medication of breast cancer, the current approaches are limited to few symptoms. More research on identifying mechanisms that can suppress breast tumor cells especially ROR1 and HER2 gene pathways is necessary to improve immune response among breast cancer patients. It is important to evaluate clinical application, particularly increasing the efficacy of nanoparticle-based siRNA technology or vaccine-related protection. Future development in cancer research requires novel nanoparticle strategies to deliver siRNA molecules more effectively to target specific tumor cells.
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