Metastasis Suppressor Genes: Basic Biology and Potential Clinical Use

Steeg, Patricia S.; Ouatas, Taoufik; Halverson, David; Palmieri, Diane; Salerno, Massimiliano

doi:10.3816/cbc.2003.n.012

Cited by 136 publications

(112 citation statements)

References 115 publications

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“…Moreover, treatment with 5-aza-2′-deoxycytidine reversed the methylated status of the BRMS1 promoter allowing for increased expression of BRMS1 protein. Thus, epigenetic silencing of BRMS1 may not only be useful as potential prognostic marker, but also could possibly be used for targeted breast cancer treatment [31,58].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer

Metge

Frost

King

et al. 2008

Clin Exp Metastasis

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Breast Cancer Metastasis Suppressor 1 (BRMS1) suppresses metastasis of human breast cancer, ovarian cancer and melanoma in athymic mice. Studies have also shown that BRMS1 is significantly downregulated in some breast tumors, especially in metastatic disease. However, the mechanisms which regulate BRMS1 expression are currently unknown. Upon examination of the BRMS1 promoter region by methylation specific PCR (MSP) analysis, we discovered a CpG island (−3477 to −2214), which was found to be hypermethylated across breast cancer cell lines. A panel of 20 patient samples analyzed showed that 45% of the primary tumors and 60% of the matched lymph node metastases, displayed hypermethylation of BRMS1 promoter. Furthermore, we found a direct correlation between the methylation status of the BRMS1 promoter in the DNA isolated from tissues, with the loss of BRMS1 expression assessed by immunohistochemistry. There are several studies investigating the mechanism by which BRMS1 suppresses metastasis; however thus far there is no

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Section: Discussionmentioning

confidence: 99%

Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer

Metge

Frost

King

et al. 2008

Clin Exp Metastasis

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“…Nm23-H1, which has DNase activity (Fan et al, 2003), is primarily cytoplasmic, whereas Nm23-H2 is both nuclear and cytoplasmic, and binds DNA (Postel et al, 2000;Bosnar et al, 2004Bosnar et al, , 2009). Identified as the first metastasis suppressor, decreased expression of Nm23-H1 is associated with higher tumor grade and increased metastasis (MacDonald et al, 1993;Steeg et al, 1998Steeg et al, , 2003. Exogenous expression of Nm23-H1 results in decreased migration in vitro and metastasis in vivo.…”

Section: Introductionmentioning

confidence: 99%

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

et al. 2010

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Plakoglobin (c-catenin) is a homolog of b-catenin with similar dual adhesive and signaling functions. The adhesive function of these proteins is mediated by their interactions with cadherins, whereas their signaling activity is regulated by association with various intracellular partners. In this respect, b-catenin has a well-defined oncogenic activity through its role in the Wnt signaling pathway, whereas plakoglobin acts as a tumor/metastasis suppressor through mechanisms that remain unclear. We previously expressed plakoglobin in SCC9 squamous carcinoma cells (SCC9-P) and observed a mesenchymalto-epidermoid transition. Comparison of the protein and RNA profiles of parental SCC9 cells and SCC9-P transfectants identified various differentially expressed proteins and transcripts, including the nonmetastatic protein 23 (Nm23). In this study, we show that Nm23-H1 mRNA and Nm23-H2 protein are increased after plakoglobin expression. Coimmunoprecipitation and confocal microscopy studies using SCC9-P and various epithelial cell lines with endogenous plakoglobin expression revealed that Nm23 interacts with plakoglobin, cadherins and a-catenin. Furthermore, Nm23-H2 is the primary isoform involved in these interactions, which occur prominently in the cytoskeleton-associated pool of cellular proteins. In addition, we show that plakoglobinNm23 interaction requires the N-terminal (a-catenin interacting) domain of plakoglobin. Our data suggest that by increasing the expression and stability of Nm23, plakoglobin has a role in regulating the metastasis suppressor activity of Nm23, which may further provide a potential mechanism for the tumor/metastasis suppressor function of plakoglobin itself.

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“…Metastasis involves a complex process through which malignant cancer cells leave a primary organ site, journey to a distant site via circulation, and finally establish a clinically detectable mass in a distant organ, and therefore, the metastatic progression requires dysregulation of a series of genes and related signaling. Metastasis suppressor genes are negative regulators of metastasis, which inhibit metastasis but do not affect the ability of the transformed cells to generate a tumor at the primary site (1)(2)(3)(4). More than 20 metastasis suppressors have been discovered so far, and they appear to be involved in several pivotal steps of metastasis, including invasion (NM23, DLC1, KAI1, and NDRG1), dissemination (KAI1, CD44), survival (BRMS1, caspase-8), and growth in distant sites (NM23, KAI1, RHOGD12, KISS1, Raf kinase inhibitor protein, and MKK4/6) (4 -7).…”

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confidence: 99%

KAI1 Gene Is Engaged in NDRG1 Gene-mediated Metastasis Suppression through the ATF3-NFκB Complex in Human Prostate Cancer

Iiizumi‐Gairani

Okuda

et al. 2011

Journal of Biological Chemistry

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Metastasis Suppressor Genes: Basic Biology and Potential Clinical Use

Cited by 136 publications

References 115 publications

Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer

Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

KAI1 Gene Is Engaged in NDRG1 Gene-mediated Metastasis Suppression through the ATF3-NFκB Complex in Human Prostate Cancer

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