The RE-1 silencer of transcription (REST) is a transcriptional regulator that represses neuron-specific genes in non-neuronal tissues by remodeling chromatin structure. We have utilized human mesenchymal stem cells ( Adult and embryonic stem cells both show therapeutic potential for many diseases (1-7). In addition, stem cells provide invaluable experimental resources to study developmental processes, including embryogenesis, cancer development, and aging (8 -10). These in vivo processes are recapitulated in vitro in investigational models. Mesenchymal stem cells (MSCs) 3 are found in fetal tissues and in adults (11). Bone marrow (BM) is the primary residence of MSCs in adults (11). MSCs can transdifferentiate into several specialized cells, including functional neuronal cells, by in vitro methods (12). Transdifferentiation is the process whereby a cell of one defined germ layer, such as mesoderm, differentiates into a cell of a different germ layer, such as ectoderm. MSCs differentiate along multilineages to generate cells of osteogenic, chondrogenic, and adipogenic types (11). MSCs have been shown to exhibit plasticity by generating specialized cells of all germ layers. However, as stem cells, it is unclear how MSCs can prevent premature expression of tissue-specific genes. The RE-1 silencer of transcription (REST), also known as neural restrictive silencing factor, is a transcription factor that represses target gene transcription by binding regulatory elements containing a consensus 21-bp RE-1 sequence (13). Repression occurs through assembly of a repressor complex at the N and C termini of the transcription factor (14). The N terminus recruits Sin3A/ histone deacetylase (HDAC), and the C terminus recruits the corepressor Co-REST to mediate chromatin remodeling and repression of gene expression (14). REST expression has been demonstrated in non-neuronal, neural stem, and neural progenitor cells, where its function has been ascribed to repressing the expression of pan-neuronal genes in non-neuronal or immature neuronal tissues (15). Recently, REST has been shown to exhibit both tumor suppressor and oncogenic activities, thus implicating its role in developmental processes (16,17). In non-neuronal, neural stem, and neural progenitor cells, REST suppresses genes exclusive to mature neurons (18). More specifically, REST silences target genes involved in synaptogenesis, progression of the cell cycle, neurotransmitter biosynthesis, and electrophysiological function (18). Down-regulation of REST is consistent with neuronal maturation and increased expression of neuron-specific genes.REST has been shown to modulate the expression of the neurotransmitter gene TAC1 (also known as preprotachykinin A) in a rodent hippocampal seizure model (19). One of the major encoded peptides of TAC1 is the neurotransmitter substance P, which belongs to the tachykinin family of neuropeptides (20). Repression of TAC1 has also been reported to occur through an NFB-dependent mechanism in non-neuronal BM stromal cells (21). * This work ...

Substance P and its truncated receptor exert oncogenic effects. The high production of substance P in breast cancer cells (BCCs) is caused by the enhancement of tachykinin (TAC)1 translation by cytosolic factor. In vitro translational studies and mRNA stabilization analyses indicate that BCCs contain the factor needed to increase TAC1 translation and to stabilize the mRNA. Prediction of protein folding, RNA-shift analysis, and proteomic analysis identified a 40 kDa molecule that interacts with the noncoding exon 7. Western blot analysis and RNA supershift identified Musashi 1 (Msi1) as the binding protein. Ectopic expression of TAC1 in nontumorigenic breast cells (BCs) indicates that TAC1 regulates its stability by increasing Msi1. Using a reporter gene system, we showed that Msi1 competes with microRNA (miR)130a and -206 for the 3' UTR of exon 7/TAC1. In the absence of Msi1 and miR130a and -206, reporter gene activity decreased, indicating that Msi1 expression limits TAC1 expression. Tumor growth was significantly decreased when nude BALB/c mice were injected with Msi1-knockdown BCCs. In summary, the RNA-binding protein Msi1 competes with miR130a and -206 for interaction with TAC1 mRNA, to stabilize and increase its translation. Consequently, these interactions increase tumor growth.

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Among all cancers, malignancies of the breast are the second leading cause of cancer death in the United States after carcinoma of the lung. One of the major factors considered when assessing the prognosis of breast cancer patients is whether the tumor has metastasized to distant organs. Although the exact phenotype of the malignant cells responsible for metastasis and dormancy is still unknown, growing evidence has revealed that they may have stem cell-like properties that may account for resistance to chemotherapy and radiation. One process that has been attributed to primary tumor metastasis is the epithelial-to-mesenchymal transition. In this review, we specifically discuss breast cancer dissemination to the bone marrow and factors that ultimately serve to shelter and promote tumor growth, including the complex relationship between mesenchymal stem cells (MSCs) and various aspects of the immune system, carcinoma-associated fibroblasts, and the diverse components of the tumor microenvironment. A better understanding of the journey from the primary tumor site to the bone marrow and subsequently the oncoprotective role of MSCs and other factors within that microenvironment can potentially lead to development of novel therapeutic targets.