Background: The process of malignant transformation, progression and metastasis of melanoma is poorly understood. Gene expression profiling of human cancer has allowed for a unique insight into the genes that are involved in these processes. Thus, we have attempted to utilize this approach through the analysis of a series of primary, non-metastatic cutaneous tumors and metastatic melanoma samples.

The rapid development of new anticancer drugs that are safe and effective is a common goal shared by basic scientists, clinicians and patients. The current review discusses one such agent, namely niclosamide, which has been used in the clinic for the treatment of intestinal parasite infections. Recent studies repeatedly identified niclosamide as a potential anticancer agent by various high-throughput screening campaigns. Niclosamide not only inhibits the Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce cell cycle arrest, growth inhibition and apoptosis. A number of studies have established the anticancer activities of niclosamide in both in vitro and in vivo models. Moreover, the inhibitory effects of niclosamide on cancer stem cells provide further evidence for its consideration as a promising drug for cancer therapy. This article reviews various aspects of niclosamide as they relate to its efficacy against cancer and associated molecular mechanisms.

Osteopontin (OPN) is a multifunctional cytokine that impacts cell proliferation, survival, drug resistance, invasion, and stem like behavior. Due to its critical involvement in regulating cellular functions, its aberrant expression and/or splicing is functionally responsible for undesirable alterations in disease pathologies, specifically cancer. It is implicated in promoting invasive and metastatic progression of many carcinomas. Due to its autocrine and paracrine activities OPN has been shown to be a crucial mediator of cellular cross talk and an influential factor in the tumor microenvironment. OPN has been implicated as a prognostic and diagnostic marker for several cancer types. It has also been explored as a possible target for treatment. In this article we hope to provide a broad perspective on the importance of OPN in the pathophysiology of cancer.

Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis of multiple human and murine cancer cells without inhibiting tumorigenicity. By yeast two-hybrid and co-immunoprecipitation, BRMS1 interacts with retinoblastoma binding protein 1 and at least seven members of the mSin3 histone deacetylase (HDAC) complex in human breast and melanoma cell lines. BRMS1 co-immunoprecipitates enzymatically active HDAC proteins and represses transcription when recruited to a Gal4 promoter in vivo. BRMS1 exists in large mSin3 complex(es) of ϳ1.4 -1.9 MDa, but also forms smaller complexes with HDAC1. Deletion analyses show that the carboxyl-terminal 42 amino acids of BRMS1 are not critical for interaction with much of the mSin3 complex and that BRMS1 appears to have more than one binding point to the complex. These results further show that BRMS1 may participate in transcriptional regulation via interaction with the mSin3⅐HDAC complex and suggest a novel mechanism by which BRMS1 might suppress cancer metastasis.The complex process of cancer cell dissemination and the establishment of secondary foci involves the acquisition of multiple abilities by metastatic cells. For example, blood-borne metastasis requires cells to invade from the primary tumor, enter the circulation, survive transport, arrest at a secondary site, recruit a blood supply, and proliferate at that site (1). The ability to accomplish all of these steps likely involves changes in, and coordinated expression of, a large assortment of genes. Consistent with this notion, several genes, proteins, and pathways have been associated with metastatic progression, including oncogenes, motility factors, and matrix metalloproteinases (1, 2). In addition to metastasis-promoting genes, a new class of molecules called metastasis suppressors has been described (reviewed in Refs. 2-5). By definition, metastasis suppressors inhibit metastasis without blocking primary tumor growth, presumably by inhibiting one or more steps necessary for metastasis. To date, 13 metastasis suppressor genes have been identified that reduce the metastatic ability of cancer cell line(s) in vivo without affecting tumorigenicity, namely breast cancer metastasis suppressor 1 (BRMS1), 1 CRSP3, DRG1, KAI1, KISS1, MKK4, NM23, RhoGDI2, RKIP, SSeCKs, VDUP1, E-cadherin, and TIMPs (reviewed in Refs. 4 and 5).We identified BRMS1 using differential display to compare highly metastatic breast carcinoma cells with related but metastasis-suppressed cells (6). Enforced expression of BRMS1 suppressed metastasis in three animal models, namely human breast (6), murine mammary (7), and human melanoma cells (8). Additionally, BRMS1 mapped to loci in murine (7) and human (6) genomes that had previously been implicated in metastasis control (9). The BRMS1 protein localized to nuclei and restored gap junctional intercellular communication in both breast and melanoma tumor cell lines (8,10,11), but its molecular functions remain to be elucidated.One approach to determine a mechanism of action involves identifying which...

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The role of Hedgehog (Hh) signaling as a developmental pathway is well established. Several recent studies have implicated a role for this pathway in multiple cancers. In this study we report that expression of GLI1 and osteopontin (OPN) increase progressively with the progression of melanoma from primary cutaneous cancer to metastatic melanoma in clinically derived specimens. We have further determined that OPN is a direct transcriptional target of GLI1. We have observed that OPN expression is stimulated in the presence of Hh ligands and inhibited in the presence of the Smoothened (SMO) inhibitor, cyclopamine. Transcriptional silencing of GLI1 negatively impacts OPN expression and compromises the ability of cancer cells to proliferate, migrate, and invade in vitro and interferes with their ability to grow as xenografts and spontaneously metastasize in nude mice. These altered attributes could be rescued by re-expressing OPN in the GLI1-silenced cells, suggesting that OPN is a critical downstream effector of active GLI1 signaling. Our observations lead us to conclude that the GLI1-mediated upregulation of OPN promotes malignant behavior of cancer cells.

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Introduction Mammalian relative of DnaJ (MRJ [DNAJB6]), a novel member of the human DnaJ family, has two isoforms. The smaller isoform, MRJ(S), is studied mainly for its possible role in Huntington's disease. There are no reports of any biologic activity of the longer isoform, MRJ(L). We investigated whether this molecule plays any role in breast cancer. Our studies were prompted by interesting observations we made regarding the expression of MRJ in breast cancer cell lines and breast cancer tissue microarrays, as described below.