Gene Summary

Gene:BRMS1; breast cancer metastasis suppressor 1
Summary:This gene reduces the metastatic potential, but not the tumorogenicity, of human breast cancer and melanoma cell lines. The protein encoded by this gene localizes primarily to the nucleus and is a component of the mSin3a family of histone deacetylase complexes (HDAC). The protein contains two coiled-coil motifs and several imperfect leucine zipper motifs. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:breast cancer metastasis-suppressor 1
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • DNA Methylation
  • Messenger RNA
  • Signal Transduction
  • Tumor Burden
  • Cell Movement
  • Proteins
  • Promoter Regions
  • Molecular Sequence Data
  • NF-kappa B
  • Tumor Suppressor Gene
  • MicroRNAs
  • Amino Acid Sequence
  • Melanoma
  • Neoplasm Invasiveness
  • Gene Expression Profiling
  • Neoplasm Proteins
  • Estrogen Receptors
  • Chromosome 11
  • alpha-Crystallin B Chain
  • Breast Cancer
  • Mutation
  • Apoptosis
  • Repressor Proteins
  • Gene Expression
  • Paranasal Sinus Neoplasms
  • Lung Cancer
  • Cell Proliferation
  • Down-Regulation
  • Two-Hybrid System Techniques
  • Cancer Gene Expression Regulation
  • Western Blotting
  • Staging
  • Cell Adhesion
  • Young Adult
  • Transfection
  • Immunohistochemistry
  • Withanolides
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors
  • Neoplasm Metastasis
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BRMS1 (cancer-related)

Liu Y, Mayo MW, Xiao A, et al.
Loss of BRMS1 promotes a mesenchymal phenotype through NF-κB-dependent regulation of Twist1.
Mol Cell Biol. 2015; 35(1):303-17 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Breast cancer metastasis suppressor 1 (BRMS1) is downregulated in non-small cell lung cancer (NSCLC), and its reduction correlates with disease progression. Herein, we investigate the mechanisms through which loss of the BRMS1 gene contributes to epithelial-to-mesenchymal transition (EMT). Using a short hairpin RNA (shRNA) system, we show that loss of BRMS1 promotes basal and transforming growth factor beta-induced EMT in NSCLC cells. NSCLC cells expressing BRMS1 shRNAs (BRMS1 knockdown [BRMS1(KD)]) display mesenchymal characteristics, including enhanced cell migration and differential regulation of the EMT markers. Mesenchymal phenotypes observed in BRMS1(KD) cells are dependent on RelA/p65, the transcriptionally active subunit of nuclear factor kappa B (NF-κB). In addition, chromatin immunoprecipitation analysis demonstrates that loss of BRMS1 increases Twist1 promoter occupancy of RelA/p65 K310-a key histone modification associated with increased transcription. Knockdown of Twist1 results in reversal of BRMS1(KD)-mediated EMT phenotypic changes. Moreover, in our animal model, BRMS1(KD)/Twist1(KD) double knockdown cells were less efficient in establishing lung tumors than BRMS1(KD) cells. Collectively, this study demonstrates that loss of BRMS1 promotes malignant phenotypes that are dependent on NF-κB-dependent regulation of Twist1. These observations offer fresh insight into the mechanisms through which BRMS1 regulates the development of metastases in NSCLC.

Marino N, Collins JW, Shen C, et al.
Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines.
Clin Exp Metastasis. 2014; 31(7):771-86 [PubMed] Related Publications
Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.

Yadav DS, Chattopadhyay I, Verma A, et al.
A pilot study evaluating genetic alterations that drive tobacco- and betel quid-associated oral cancer in Northeast India.
Tumour Biol. 2014; 35(9):9317-30 [PubMed] Related Publications
The susceptibility of an individual to oral cancer is mediated by genetic factors and carcinogen-exposure behaviors such as betel quid chewing, tobacco use, and alcohol consumption. This pilot study was aimed to identify the genetic alteration in 100 bp upstream and downstream flanking regions in addition to the exonic regions of 169 cancer-associated genes by using Next Generation sequencing with aim to elucidate the molecular pathogenesis of tobacco- and betel quid-associated oral cancer of Northeast India. To understand the role of chemical compounds present in tobacco and betel quid associated with the progression of oral cancer, single nucleotide polymorphisms (SNPs) and insertion and deletion (Indels) found in this study were analyzed for their association with chemical compounds found in tobacco and betel quid using Comparative Toxogenomic Database. Genes (AR, BRCA1, IL8, and TP53) with novel SNP were found to be associated with arecoline which is the major component of areca nut. Genes (BARD1, BRCA2, CCND2, IGF1R, MSH6, and RASSF1) with novel deletion and genes (APC, BRMS1, CDK2AP1, CDKN2B, GAS1, IGF1R, and RB1) with novel insertion were found to be associated with aflatoxin B1 which is produced by fermented areca nut. Genes (ADH6, APC, AR, BARD1, BRMS1, CDKN1A, E2F1, FGFR4, FLNC, HRAS, IGF1R, IL12B, IL8, NBL1, STAT5B, and TP53) with novel SNP were found to be associated with aflatoxin B1. Genes (ATM, BRCA1, CDKN1A, EGFR, IL8, and TP53) with novel SNP were found to be associated with tobacco specific nitrosamines.

Mei P, Bai J, Shi M, et al.
BRMS1 suppresses glioma progression by regulating invasion, migration and adhesion of glioma cells.
PLoS One. 2014; 9(5):e98544 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. However, the expression and function of BRMS1 in glioma have not been reported. In this study, we investigated whether BRMS1 play a role in glioma pathogenesis. Using the tissue microarray technology, we found that BRMS1 expression is significantly decreased in glioma compared with tumor adjacent normal brain tissue (P<0.01, χ(2) test) and reduced BRMS1 staining is associated with WHO stages (P<0.05, χ(2) test). We also found that BRMS1 was significantly downregulated in glioma cell lines compared to normal human astrocytes (P<0.01, χ(2) test). Furthermore, we demonstrated that BRMS1 overexpression inhibited glioma cell invasion by suppressing uPA, NF-κB, MMP-2 expression and MMP-2 enzyme activity. Moreover, our data showed that overexpression of BRMS1 inhibited glioma cell migration and adhesion capacity compared with the control group through the Src-FAK pathway. Taken together, this study suggested that BRMS1 has a role in glioma development and progression by regulating invasion, migration and adhesion activities of cancer cells.

Hall EH, Liu Y, Xiao A, et al.
Inhibition of breast cancer metastasis suppressor 1 promotes a mesenchymal phenotype in lung epithelial cells that express oncogenic K-RasV12 and loss of p53.
PLoS One. 2014; 9(4):e95869 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Expression of the breast cancer metastasis suppressor 1 (BRMS1) protein is dramatically reduced in non-small cell lung cancer (NSCLC) cells and in primary human tumors. Although BRMS1 is a known suppressor of metastasis, the mechanisms through which BRMS1 functions to regulate cell migration and invasion in response to specific NSCLC driver mutations are poorly understood. To experimentally address this, we utilized immortalized human bronchial epithelial cells in which p53 was knocked down in the presence of oncogenic K-RasV12 (HBEC3-p53KD-K-RasV12). These genetic alterations are commonly found in NSCLC and are associated with a poor prognosis. To determine the importance of BRMS1 for cytoskeletal function, cell migration and invasion in our model system we stably knocked down BRMS1. Here, we report that loss of BRMS1 in HBEC3-p53KD-K-RasV12 cells results in a dramatic increase in cell migration and invasion compared to controls that expressed BRMS1. Moreover, the loss of BRMS1 resulted in additional morphological changes including F-actin re-distribution, paxillin accumulation at the leading edge of the lamellapodium, and cellular shape changes resembling mesenchymal phenotypes. Importantly, re-expression of BRMS1 restores, in part, cell migration and invasion; however it does not fully reestablish the epithelial phenotype. These finding suggests that loss of BRMS1 results in a permanent, largely irreversible, mesenchymal phenotype associated with increased cell migration and invasion. Collectively, in NSCLC cells without p53 and expression of oncogenic K-Ras our study identifies BRMS1 as a key regulator required to maintain a cellular morphology and cytoskeletal architecture consistent with an epithelial phenotype.

Balgkouranidou I, Chimonidou M, Milaki G, et al.
Breast cancer metastasis suppressor-1 promoter methylation in cell-free DNA provides prognostic information in non-small cell lung cancer.
Br J Cancer. 2014; 110(8):2054-62 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
BACKGROUND: Breast-cancer metastasis suppressor 1 (BRMS1) gene encodes for a predominantly nuclear protein that differentially regulates the expression of multiple genes, leading to suppression of metastasis without blocking orthotropic tumour growth. The aim of the present study was to evaluate for the first time the prognostic significance of BRMS1 promoter methylation in cell-free DNA (cfDNA) circulating in plasma of non-small cell lung cancer (NSCLC) patients. Towards this goal, we examined the methylation status of BRMS1 promoter in NSCLC tissues, matched adjacent non-cancerous tissues and corresponding cfDNA as well as in an independent cohort of patients with advanced NSCLC and healthy individuals.
METHODS: Methylation of BRMS1 promoter was examined in 57 NSCLC tumours and adjacent non-cancerous tissues, in cfDNA isolated from 48 corresponding plasma samples, in cfDNA isolated from plasma of 74 patients with advanced NSCLC and 24 healthy individuals.
RESULTS: The BRMS1 promoter was highly methylated both in operable NSCLC primary tissues (59.6%) and in corresponding cfDNA (47.9%) but not in cfDNA from healthy individuals (0%), while it was also highly methylated in cfDNA from advanced NSCLC patients (63.5%). In operable NSCLC, Kaplan-Meier estimates were significantly different in favour of patients with non-methylated BRMS1 promoter in cfDNA, concerning both disease-free interval (DFI) (P=0.048) and overall survival (OS) (P=0.007). In advanced NSCLC, OS was significantly different in favour of patients with non-methylated BRMS1 promoter in their cfDNA (P=0.003). Multivariate analysis confirmed that BRMS1 promoter methylation has a statistical significant influence both on operable NSCLC patients' DFI time and OS and on advanced NSCLC patients' PFS and OS.
CONCLUSIONS: Methylation of BRMS1 promoter in cfDNA isolated from plasma of NSCLC patients provides important prognostic information and merits to be further evaluated as a circulating tumour biomarker.

Zhang Y, Ye L, Tan Y, et al.
Expression of breast cancer metastasis suppressor-1, BRMS-1, in human breast cancer and the biological impact of BRMS-1 on the migration of breast cancer cells.
Anticancer Res. 2014; 34(3):1417-26 [PubMed] Related Publications
UNLABELLED: Breast cancer metastasis suppressor-1 (BRMS1) is a candidate metastasis-suppressing gene and has been shown to potentially inhibit tumor progression without blocking the growth of orthotopic tumors, in different tumor types including non-small cell lung cancer, ovarian, melanoma and breast cancers.
MATERIALS AND METHODS: BRMS-1 gene transcript was quantified in breast cancer sample tissues and analyzed against histological and clinical patient outcome. Human breast cancer cell lines, MDA MB-231 and MCF-7 were used to genetically-modify the expression of BRMS-1 and test for biological responses following BRMS-1 modifications. Key candidate signal pathways, influenced by BRMS-1 were also explored.
RESULTS: BRMS1 was present in MDA MB-231 and MCF-7 cell lines. Using anti-BRMS1 transgenes, we knocked-down the transcripts of BRMS1 in both cells at the mRNA and protein levels. Knockdown of BRMS1 gave both cells a faster cell growth rate, rapid pace of cellular migration and invasion, compared to respective wild-type and control cells (p<0.05). Blocking phospholipase-Cγ (PLCγ) had a significant influence on the BRMS-1-induced cell migration. Finally, significantly low levels of BRMS1 were observed in patients with high-grade tumors (p=0.12), in patients with distant metastasis (p=0.05) and those who died of breast cancer (p=0.0037). In addition, patients with low levels of BRMS1 had a significantly shorter overall survival (p=0.035).
CONCLUSION: BRMS-1 is aberrantly expressed in human breast cancer and is inversely-correlated with disease progression and patient survival. This is likely to be occurring via its influence on invasion and migration of breast cancer cells.

Szarc vel Szic K, Op de Beeck K, Ratman D, et al.
Pharmacological levels of Withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells.
PLoS One. 2014; 9(2):e87850 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer.

Zmetakova I, Danihel L, Smolkova B, et al.
Evaluation of protein expression and DNA methylation profiles detected by pyrosequencing in invasive breast cancer.
Neoplasma. 2013; 60(6):635-46 [PubMed] Related Publications
Breast carcinoma is the most common cancer with high mortality caused by metastatic disease. New molecular biomarkers predicting the tumour's metastatic potential would therefore improve metastasis prevention and personalised care. The aim of the study was to investigate the relationship between DNA methylation levels in invasivity and metastasising associated genes with aberrant protein expression and also to evaluate whether a similar DNA methylation level is present in the tumour and circulating cell-free DNA for utilising plasma DNA methylation as prognostic biomarker. By using pyrosequencing, we analysed DNA methylation levels of 11 genes, namely APC, ADAM23, CXCL12, ESR1, PGR B, CDH1, RASSF1A, SYK, TIMP3, BRMS1 and SOCS1 in tumour, plasma and peripheral blood cells from 34 patients with primary breast cancer, as well as plasma and peripheral blood cells from 50 healthy controls. Simultaneously, the expression of related proteins in paraffin-embedded tumour samples was evaluated by immunohistochemistry. Statistical analysis was performed by SPSS statistics 15.0 software. Tumour DNA hypermethylation was found in most commonly methylated RASSF1A (71.9%), APC (55.9%), ADAM23 (38%) and CXCL12 (34.4%) genes with methylation levels up to 86, 86, 53 and 64 %, respectively. In tumours, significantly higher methylation levels were found in nine genes, compared with the patients´ peripheral blood cell DNA. Furthermore, in patients methylation levels in peripheral blood cell DNA were significantly higher than in controls in CXCL12, ESR1 and TIMP3 genes, but the values did not exceed 15%. On the other hand, no correlations were observed in patients between DNA methylation in tumours and cell-free plasma DNA. Moreover, in patients and controls nearly identical values of cumulative DNA methylation (43.6 % ± 20.1 vs. 43.7 % ± 15.0) were observed in plasma samples. A variable spectrum from high to none expressions presented in tumour tissues in all of the proteins evaluated, however in APC and CXCL12 genes a visible decreasing trend of mean DNA methylation level with increasing expression of the corresponding protein was observed. The DNA methylation profiles manifested in our group of breast carcinomas are cancer specific, but they are not the only cause that affects the silencing of evaluated genes and the decrease of relevant protein products. The clinical utility of DNA methylation testing in peripheral blood cell DNA for cancer diagnosis and therapy need to be further investigated.

Roberts MR, Hong CC, Edge SB, et al.
Case-only analyses of the associations between polymorphisms in the metastasis-modifying genes BRMS1 and SIPA1 and breast tumor characteristics, lymph node metastasis, and survival.
Breast Cancer Res Treat. 2013; 139(3):873-85 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Lymph node metastases and tumor characteristics predict breast cancer prognosis but correlate imperfectly with likelihood of metastatic relapse. Discovery of genetic polymorphisms affecting metastasis may improve identification of patients requiring aggressive adjuvant therapy to prevent recurrence. We investigated associations between several variants in the BRMS1 and SIPA1 metastasis-modifying genes and lymph node metastases, tumor subtype and grade, recurrence, disease-free survival, and overall survival. This cross-sectional and prospective prognostic analysis included 859 patients who received surgery for incident breast cancer at Roswell Park Cancer Institute, participated in the DataBank and BioRepository shared resource, and had DNA, clinical, and pathology data available for analysis. Genotyping for BRMS1 (rs11537993, rs3116068, and rs1052566) and SIPA1 (rs75894763, rs746429, rs3741378, and rs2306364) polymorphisms was performed using Sequenom(®) iPLEX Gold and Taqman(®) real-time PCR assays. Logistic and Cox proportional hazards regressions were used to estimate odds ratios (OR) and hazard ratios (HR), respectively. BRMS1 rs1052566 heterozygous individuals were more likely to have node-positive tumors (OR = 1.58, 95 % CI 1.13-2.23), although there was no dose-response relationship, and those with at least one variant allele were less likely to have the luminal B subtype (AG + AA: OR = 0.59, 95 % CI 0.36-0.98). BRMS1 rs3116068 was associated with increased likelihood of having the luminal B and the HER2-enriched tumor subtype (P trend = 0.03). Two SIPA1 SNPs, rs746429 and rs2306364, were associated with decreased risk of triple-negative tumors (P trend = 0.04 and 0.07, respectively). Presence of 8 or more risk alleles was associated with an increased likelihood of having a node-positive tumor (OR = 2.14, 95 % CI 1.18-3.36, P trend = 0.002). There were no significant associations with survival. Polymorphisms in metastasis-associated genes may be related to tumor characteristics and lymph node metastasis, but not survival. Future evaluation of metastasis-modifying gene variants is necessary to better understand the biology of metastasis.

Chimonidou M, Kallergi G, Georgoulias V, et al.
Breast cancer metastasis suppressor-1 promoter methylation in primary breast tumors and corresponding circulating tumor cells.
Mol Cancer Res. 2013; 11(10):1248-57 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
UNLABELLED: Breast cancer metastasis suppressor-1 (BRMS1) differentially regulates the expression of multiple genes, leading to metastasis suppression without affecting orthotopic tumor growth. For the first time, BRMS1 promoter methylation was evaluated as a prognostic biomarker in primary breast tumors and a subset of corresponding circulating tumor cells (CTC). Formalin-fixed paraffin embedded samples were analyzed for BRMS1 methylation status using methylation-specific PCR in a human specimen cohort consisting of noncancerous tissues, benign fibroadenomas, and primary breast tumors, including some with adjacent noncancerous tissues. Peripheral blood mononuclear cells from a large subset of these patients were fixed in cytospins and analyzed. In addition, BRMS1 expression in cytospins was examined by double-immunofluorescence using anti-BRMS1 and pan-cytokeratin antibodies. BRMS1 promoter methylation was not detected in noncancerous breast tissues or benign fibroadenomas; however, methylation was observed in more than a third of primary breast tumors. Critically, BRMS1 promoter methylation in primary tumors was significantly associated with reduced disease-free survival with a trend toward reduced overall survival. Similarly, a third of cytospin samples were positive for the presence of CTCs, and the total number of detected CTCs was 41. Although a large fraction of CTCs were negative or maintained low expression of BRSM1, promoter methylation was observed in a small fraction of samples, implying that BRSM1 expression in CTCs was either downregulated or heterogeneous. In summary, these data define BRMS1 promoter methylation in primary breast tumors and associated CTCs.
IMPLICATIONS: This study indicates that BRSM1 promoter methylation status has biomarker potential in breast cancer.

Wu J, Wang Y, Qiao X, et al.
Cloning and characterization of a novel human BRMS1 transcript variant in hepatocellular carcinoma cells.
Cancer Lett. 2013; 337(2):266-75 [PubMed] Related Publications
Breast cancer metastasis suppressor 1 (BRMS1) is able to suppress tumor metastasis without affecting primary tumor growth in various cancers. Here, we report a novel transcript variant of human BRMS1, termed BRMS1.vh. BRMS1.vh is identical to the major BRMS1 variant (BRMS1.v1) except for missing base pairs 683-775, encoding a 215-amino acid protein lacking a functional nuclear localization sequence. Expression of BRMS1.vh in hepatocellular carcinoma (HCC) cells suppressed NF-κB signaling pathway, sensitized cells to apoptotic stimuli, leading to suppressed tumor growth. Taken together, our results suggest a potential role for BRMS1.vh in regulating cell apoptosis and tumor growth in HCC.

Tzadok S, Caspin Y, Hachmo Y, et al.
Directionality of noncoding human RNAs: how to avoid artifacts.
Anal Biochem. 2013; 439(1):23-9 [PubMed] Related Publications
Inactivation of tumor suppressor and metastasis suppressor genes via epigenetic silencing is a frequent event in human cancers. Recent work has shown new mechanisms of epigenetic silencing, based on the occurrence of long noncoding promoter-spanning antisense and/or sense RNAs (lncRNAs), which constitute part of chromatin silencing complexes. Using reverse transcription polymerase chain reaction (RT-PCR), we have started to scan "triple negative" and Her2-overexpressing breast cancer cell lines for directional/bidirectional transcription through promoters of tumor suppressor and metastasis suppressor genes known to be epigenetically silenced in vivo. Surprisingly, we found that RT-PCR-amplified products were obtained at high frequency in the absence of exogenous primers. These amplified products resulted from RT priming via transcripts originating from promoter or upstream spanning regions. Consequently, this priming overruled directionality determination and led to false detection-identification of such lncRNAs. We show that this prevalent "no primer" artifact can be eliminated by treating the RNA preparations with periodate, performing RT reactions at highly elevated temperatures, or a combination of both. These experimental improvements enabled determination of the presence and directionality of individual promoter-spanning long noncoding RNAs with certainty. Examples for the BRMS1 metastasis suppressor gene, as well as RAR-β2 and CST6 human tumor suppressor genes, in breast carcinoma cell lines are presented.

Hurst DR, Xie Y, Thomas JW, et al.
The C-terminal putative nuclear localization sequence of breast cancer metastasis suppressor 1, BRMS1, is necessary for metastasis suppression.
PLoS One. 2013; 8(2):e55966 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Breast cancer metastasis suppressor 1 (BRMS1) is a predominantly nuclear protein that suppresses metastasis in multiple human and murine carcinoma cell lines. BRMS1 interacts with several nuclear proteins including SIN3:HDAC chromatin remodeling complexes that are involved in repressing transcription. However, recent reports suggest BRMS1 may function in the cytoplasm. BRMS1 has two predicted nuclear localization sequences (NLS) that are located near the C-terminus (amino acids 198-205 and 238-244, NLS1 and NLS2 respectively). We hypothesized that nuclear localization sequences of BRMS1 were essential for BRMS1 mediated metastasis suppression. Replacement of NLS2 with NLS1 (BRMS1(NLS1,1)), truncation at 238 (BRMS1(ΔNLS2)), or switching the location of NLS1 and NLS2 (BRMS1(NLS2,1)) did not affect nuclear localization; but, replacement of NLS1 with NLS2 (BRMS1(NLS2,2)) or truncation at 197 (BRMS1(ΔNLS) which removes both NLS) promoted cytoplasmic localization. MDA-MB-231 human metastatic breast cancer cells transduced with BRMS1(NLS1,1), BRMS1(NLS2,2) or BRMS1(NLS2,1) were evaluated for metastasis suppression in an experimental xenograft mouse model. Interestingly, while NLS2 was not necessary for nuclear localization, it was found to be important for metastasis suppression since BRMS1(NLS2,2) suppressed metastasis by 85%. In contrast, BRMS1(NLS2,1) and BRMS1(NLS1,1) did not significantly suppress metastasis. Both BRMS1 and BRMS1(NLS2,2) co-immunoprecipitated with SIN3A in the nucleus and cytoplasm; however, BRMS1(NLS1,1) and BRMS1(NLS2,1) were associated with SIN3A in the nucleus only. Moreover, BRMS1 and BRMS1(NLS2,2), but not BRMS1(NLS1,1) and BRMS1(NLS2,1), down-regulated the pro-metastatic microRNA, miR-10b. Together, these data demonstrate an important role for NLS2 in the cytoplasm that is critical for metastasis suppression and is distinct from nuclear localization.

Liu Y, Mayo MW, Nagji AS, et al.
BRMS1 suppresses lung cancer metastases through an E3 ligase function on histone acetyltransferase p300.
Cancer Res. 2013; 73(4):1308-17 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
The mechanisms through which the metastasis suppressor gene BRMS1 functions are poorly understood. Herein, we report the identification of a previously undescribed E3 ligase function of BRMS1 on the histone acetyltransferase p300. BRMS1 induces polyubiquitination of p300, resulting in its proteasome-mediated degradation. We identify BRMS1 as the first eukaryote structural mimic of the bacterial IpaH E3 ligase family and establish that the evolutionarily conserved CXD motif located in BRMS1 is responsible for its E3 ligase function. Mutation of this E3 ligase motif not only abolishes BRMS1-induced p300 polyubiquitination and degradation, but importantly, dramatically reduces the metastasis suppressor function of BRMS1 in both in vitro and in vivo models of lung cancer metastasis.

Cui RX, Liu N, He QM, et al.
Low BRMS1 expression promotes nasopharyngeal carcinoma metastasis in vitro and in vivo and is associated with poor patient survival.
BMC Cancer. 2012; 12:376 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
BACKGROUND: Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene. This study aimed to investigate the impact of BRMS1 on metastasis in nasopharyngeal carcinoma (NPC) and to evaluate the prognostic significance of BRMS1 in NPC patients.
METHODS: BRMS1 expression was examined in NPC cell lines using quantitative reverse transcription-polymerase chain reaction and Western blotting. NPC cells stably expressing BRMS1 were used to perform wound healing and invasion assays in vitro and a murine xenograft assay in vivo. Immunohistochemical staining was performed in 274 paraffin-embedded NPC specimens divided into a training set (n = 120) and a testing set (n = 154).
RESULTS: BRMS1 expression was down-regulated in NPC cell lines. Overexpression of BRMS1 significantly reversed the metastatic phenotype of NPC cells in vitro and in vivo. Importantly, low BRMS1 expression was associated with poor distant metastasis-free survival (DMFS, P < 0.001) and poor overall survival (OS, P < 0.001) in the training set; these results were validated in the testing set and overall patient population. Cox regression analysis demonstrated that low BRMS1 expression was an independent prognostic factor for DMFS and OS in NPC.
CONCLUSIONS: Low expression of the metastasis suppressor BRMS1 may be an independent prognostic factor for poor prognosis in NPC patients.

Wu Y, Jiang W, Wang Y, et al.
Breast cancer metastasis suppressor 1 regulates hepatocellular carcinoma cell apoptosis via suppressing osteopontin expression.
PLoS One. 2012; 7(8):e42976 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Breast cancer metastasis suppressor 1 (BRMS1) was originally identified as an active metastasis suppressor in human breast cancer. Loss of BRMS1 expression correlates with tumor progression, and BRMS1 suppresses several steps required for tumor metastasis. However, the role of BRMS1 in hepatocellular carcinoma (HCC) remains elusive. In this study, we found that the expression level of BRMS1 was significantly down-regulated in HCC tissues. Expression of BRMS1 in SK-Hep1 cells did not affect cell growth under normal culture conditions, but sensitized cells to apoptosis induced by serum deprivation or anoikis. Consistently, knockdown of endogenous BRMS1 expression in Hep3B cells suppressed cell apoptosis. We identified that BRMS1 suppresses osteopontin (OPN) expression in HCC cells and that there is a negative correlation between BRMS1 and OPN mRNA expression in HCC tissues. Moreover, knockdown of endogenous OPN expression reversed the anti-apoptosis effect achieved by knockdown of BRMS1. Taken together, our results show that BRMS1 sensitizes HCC cells to apoptosis through suppressing OPN expression, suggesting a potential role of BRMS1 in regulating HCC apoptosis and metastasis.

Winter SF, Lukes L, Walker RC, et al.
Allelic variation and differential expression of the mSIN3A histone deacetylase complex gene Arid4b promote mammary tumor growth and metastasis.
PLoS Genet. 2012; 8(5):e1002735 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Accumulating evidence suggests that breast cancer metastatic progression is modified by germline polymorphism, although specific modifier genes have remained largely undefined. In the current study, we employ the MMTV-PyMT transgenic mouse model and the AKXD panel of recombinant inbred mice to identify AT-rich interactive domain 4B (Arid4b; NM_194262) as a breast cancer progression modifier gene. Ectopic expression of Arid4b promoted primary tumor growth in vivo as well as increased migration and invasion in vitro, and the phenotype was associated with polymorphisms identified between the AKR/J and DBA/2J alleles as predicted by our genetic analyses. Stable shRNA-mediated knockdown of Arid4b caused a significant reduction in pulmonary metastases, validating a role for Arid4b as a metastasis modifier gene. ARID4B physically interacts with the breast cancer metastasis suppressor BRMS1, and we detected differential binding of the Arid4b alleles to histone deacetylase complex members mSIN3A and mSDS3, suggesting that the mechanism of Arid4b action likely involves interactions with chromatin modifying complexes. Downregulation of the conserved Tpx2 gene network, which is comprised of many factors regulating cell cycle and mitotic spindle biology, was observed concomitant with loss of metastatic efficiency in Arid4b knockdown cells. Consistent with our genetic analysis and in vivo experiments in our mouse model system, ARID4B expression was also an independent predictor of distant metastasis-free survival in breast cancer patients with ER+ tumors. These studies support a causative role of ARID4B in metastatic progression of breast cancer.

Hurst DR
Metastasis suppression by BRMS1 associated with SIN3 chromatin remodeling complexes.
Cancer Metastasis Rev. 2012; 31(3-4):641-51 [PubMed] Related Publications
Epigenetic regulation of gene transcription by histone modification and chromatin remodeling has been linked to many biological and pathological events including cancer metastasis. Breast cancer metastasis suppressor 1 (BRMS1) interacts with SIN3 chromatin remodeling complexes, and, upon forced expression in metastatic cells, a nearly complete suppression of metastasis is noted without preventing primary tumor growth. The data for BRMS1-mediated metastasis suppression and SIN3 interaction are clear; however, connecting the inhibition directly to the association of BRMS1 with SIN3 complexes is currently not well defined. Considering the recent advancements in developing epigenetic drugs for cancer therapy, an improved understanding of how the interactions between BRMS1 and SIN3 regulate the process of metastasis should lead to novel therapies specifically targeting the most deadly aspect of tumor progression. In this article, the data for BRMS1-mediated metastasis suppression are reviewed with a focus on how the SIN3 chromatin remodeling complexes may be functionally involved.

Slipicevic A, Holm R, Emilsen E, et al.
Cytoplasmic BRMS1 expression in malignant melanoma is associated with increased disease-free survival.
BMC Cancer. 2012; 12:73 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
BACKGROUND/AIMS: Breast cancer metastasis suppressor 1 (BRMS1) blocks metastasis in melanoma xenografts; however, its usefulness as a biomarker in human melanomas has not been widely studied. The goal was to measure BRMS1 expression in benign nevi, primary and metastatic melanomas and evaluate its impact on disease progression and prognosis.
METHODS: Paraffin-embedded tissue from 155 primary melanomas, 69 metastases and 15 nevi was examined for BRMS1 expression using immunohistochemistry. siRNA mediated BRMS1 down-regulation was used to study impact on invasion and migration in melanoma cell lines.
RESULTS: A significantly higher percentage of nevi (87%), compared to primary melanomas (20%) and metastases (48%), expressed BRMS1 in the nucelus (p < 0.0001). Strong nuclear staining intensity was observed in 67% of nevi, and in 9% and 24% of the primary and metastatic melanomas, respectively (p < 0.0001). Comparable cytoplasmic expression was observed (nevi; 87%, primaries; 86%, metastases; 72%). However, a decline in cytoplasmic staining intensity was observed in metastases compared to nevi and primary tumors (26%, 47%, and 58%, respectively, p < 0.0001). Score index (percentage immunopositive celles multiplied with staining intensity) revealed that high cytoplasmic score index (≥ 4) was associated with thinner tumors (p = 0.04), lack of ulceration (p = 0.02) and increased disease-free survival (p = 0.036). When intensity and percentage BRMS1 positive cells were analyzed separately, intensity remained associated with tumor thickness (p = 0.024) and ulceration (p = 0.004) but was inversely associated with expression of proliferation markers (cyclin D3 (p = 0.008), cyclin A (p = 0.007), and p21Waf1/Cip1 (p = 0.009)). Cytoplasmic score index was inversely associated with nuclear p-Akt (p = 0.013) and positively associated with cytoplasmic p-ERK1/2 expression (p = 0.033). Nuclear BRMS1 expression in ≥ 10% of primary melanoma cells was associated with thicker tumors (p = 0.016) and decreased relapse-free period (p = 0.043). Nuclear BRMS1 was associated with expression of fatty acid binding protein 7 (FABP7; p = 0.011), a marker of invasion in melanomas. In line with this, repression of BRMS1 expression reduced the ability of melanoma cells to migrate and invade in vitro.
CONCLUSION: Our data suggest that BRMS1 is localized in cytoplasm and nucleus of melanocytic cells and that cellular localization determines its in vivo effect. We hypothesize that cytoplasmic BRMS1 restricts melanoma progression while nuclear BRMS1 possibly promotes melanoma cell invasion.Please see related article:

Sheng XJ, Zhou YQ, Song QY, et al.
Loss of breast cancer metastasis suppressor 1 promotes ovarian cancer cell metastasis by increasing chemokine receptor 4 expression.
Oncol Rep. 2012; 27(4):1011-8 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Breast cancer metastasis suppressor 1 (BRMS1) is a predominantly nuclear protein that differentially regulates the expression of multiple genes, leading to suppression of metastasis without affecting orthotopic tumor growth. It has been demonstrated that BRMS1 may be correlated with advanced ovarian cancer. The aim of this study was to investi-gate the mechanisms of BRMS1 involvement in ovarian cancer metastasis. We constructed a plasmid containing a short hairpin RNA (shRNA) against BRMS1 and transfected it into the ovarian cancer cell line OVCAR3. Real-time reverse transcription polymerase chain reaction (real-time PCR) and Western blot analyses demonstrated that BRMS1 expression was efficiently downregulated. Stable suppression of BRMS1 significantly enhanced cell adhesion, migration, invasion and angiogenesis. We also found that chemokine receptor 4 (CXCR4) was upregulated at both the mRNA and protein levels. When approaching for the mechanism, we discovered that activation of the nuclear factor-κB (NF-κB) signaling pathway mediated CXCR4 upregulation, as demonstrated by the electrophoretic mobility shift assay (EMSA). Collectively, these results suggest that attenuation of BRMS1 may play a critical role in promoting migration, invasion and angiogenesis of ovarian cancer cells and BRMS1 may regulate the metastatic potential at least in part through upregulation of CXCR4 via NF-κB activation. Restoration of BRMS1 function is thus a potential new strategy for treating human ovarian cancer.

Kim B, Nam HJ, Pyo KE, et al.
Breast cancer metastasis suppressor 1 (BRMS1) is destabilized by the Cul3-SPOP E3 ubiquitin ligase complex.
Biochem Biophys Res Commun. 2011; 415(4):720-6 [PubMed] Related Publications
Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis without affecting primary tumorigenesis. The regulatory mechanism of BRMS1 at the protein level has not been revealed until recently. Here, we found that cullin 3 (Cul3), a component of E3 ubiquitin ligase, is a new binding partner of BRMS1 and the interaction between BRMS1 and Cul3 is mediated by the SPOP adaptor protein. Intriguingly, BRMS1 turns out to be a potent substrate that is ubiquitinated by the Cul3-SPOP complex. Knockdown of SPOP increases the level of BRMS1 protein and represses the expression of BRMS1 repressive target genes such as OPN and uPA in breast cancer cells. These results suggest that the novel regulatory mechanism of BRMS1 by Cul3-SPOP complex is important for breast cancer progression.

Al-Alwan M, Olabi S, Ghebeh H, et al.
Fascin is a key regulator of breast cancer invasion that acts via the modification of metastasis-associated molecules.
PLoS One. 2011; 6(11):e27339 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
The actin-bundling protein, fascin, is a member of the cytoskeletal protein family that has restricted expression in specialized normal cells. However, many studies have reported the induction of this protein in various transformed cells including breast cancer cells. While the role of fascin in the regulation of breast cancer cell migration has been previously shown, the underlying molecular mechanism remained poorly defined. We have used variety of immunological and functional assays to study whether fascin regulates breast cancer metastasis-associated molecules. In this report we found a direct relationship between fascin expression in breast cancer patients and; metastasis and shorter disease-free survival. Most importantly, in vitro interference with fascin expression by loss or gain of function demonstrates a central role for this protein in regulating the cell morphology, migration and invasion potential. Our results show that fascin regulation of invasion is mediated via modulating several metastasis-associated genes. We show for the first time that fascin down-regulates the expression and nuclear translocation of a key metastasis suppressor protein known as breast cancer metastasis suppressor-1 (BRMS1). In addition, fascin up-regulates NF-kappa B activity, which is essential for metastasis. Importantly, fascin up-regulates other proteins that are known to be critical for the execution of metastasis such as urokinase-type plasminogen activator (uPA) and the matrix metalloproteases (MMP)-2 and MMP-9. This study demonstrates that fascin expression in breast cancer cells establishes a gene expression profile consistent with metastatic tumors and offers a potential therapeutic intervention in metastatic breast cancer treatment through fascin targeting.

Hurst DR, Welch DR
Unraveling the enigmatic complexities of BRMS1-mediated metastasis suppression.
FEBS Lett. 2011; 585(20):3185-90 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Expression of BRMS1 causes dramatic suppression of metastasis in multiple in vivo model systems. As we gain further insight into the biochemical mechanisms of BRMS1, we appreciate the importance of both molecular and cellular context for functional metastasis suppression. BRMS1 associates with large chromatin remodeling complexes including SIN3:HDAC which are powerful epigenetic regulators of gene expression. Additionally, BRMS1 inhibits the activity of NFκB, a well-known transcription factor that plays significant roles in tumor progression. Moreover, BRMS1 coordinately regulates the expression of metastasis-associated microRNA known as metastamir. How these biochemical mechanisms and biological pathways are linked, either directly or indirectly, and the influence of molecular and cellular context, are critical considerations for the discovery of novel therapeutic targets for the most deadly aspect of tumor progression-metastasis.

Schneider J, Gómez-Esquer F, Díaz-Gil G, et al.
mRNA expression of the putative antimetastatic gene BRMS1 and of apoptosis-related genes in breast cancer.
Cancer Genomics Proteomics. 2011 Jul-Aug; 8(4):195-7 [PubMed] Related Publications
Breast cancer metastasis suppressor-1 (BRMS1) is a putative antimetastatic gene. However, results relating its expression to the prognosis of breast cancer are still controversial, and all studies carried out to date have failed to show a relationship between the expression of BRMS1 and axillary lymph node metastasis in breast cancer. It has been recently suggested that BRMS1 may exert its physiological role through the modulation of apoptosis. In order to test this hypothesis, we studied the expression of BRMS1 and genes known to be directly related with apoptosis in human breast carcinoma. The expression of mRNA corresponding to BRMS1, BCL2, BAX, CASP3 and the apoptosis-related X-chromosome RNA binding motif (RBM) genes (RBMX, RBM3, RBM10 small and large variant) was studied by means of differential RT-PCR in 94 samples obtained from previously untreated patients with breast carcinoma. A significant (p=0.03) inverse correlation between BRMS1 mRNA expression and expression of the mRNA corresponding to the large variant of the X-chromosome RBM10 gene was found. The degree of direct correlation with another member of the X-chromosome RBM gene family, RBMX, almost attained statistical significance (p=0.06). These results point towards a possible link between BRMS1 expression and apoptosis in human breast cancer through a relationship with the expression of genes belonging to the X-chromosome RBM family.

Yang J, Shen Y, Liu B, Tong Y
Promoter methylation of BRMS1 correlates with smoking history and poor survival in non-small cell lung cancer patients.
Lung Cancer. 2011; 74(2):305-9 [PubMed] Related Publications
PURPOSE: To investigate whether methylation of BRMS1 is associated with clinical outcomes in patients with NSCLC.
METHODS: Methylation status of BRMS1 was examined in 325 NSCLC patients who were treated with surgery. We analyzed associations between the methylation of BRMS1 genes separately and available epidemiologic and clinical information including smoking status, gender, age, and histological type, or the stage of the tumor.
RESULTS: In the cohort of 325 NSCLC cases, 152 samples were identified as methylated (46.77%). Promoter methylation of BRMS1 was present only in 6 specimens (8.42%) in adjacent non-cancerous tissues (P=2.257 × 10(-14)). Patient smoking history had a positive correlation with methylation rate of BRMS1 (OR=2.508, 95%CI(1.516, 4.151)). Compared with unmethylated group, methylated group showed the lower level of BRMS1 mRNA (P=0.013). And patients with a high level of BRMS1 mRNA expression had significantly better overall survival than those with low expression (P=0.002). Multivariate Cox proportional hazard regression analysis also showed that promoter methylation of BRMS1 was significantly unfavorable prognostic factors (hazard ratio, 1.912; 95% CI, and 1.341-2.726).
CONCLUSIONS: These results provide clinical evidence to support the notion that BRMS1 is a NSCLC metastasis suppressor gene. Measuring methylation status of BRMS1 promotor is a useful marker for identifying NSCLC patients with worse disease-free survival.

Chimonidou M, Strati A, Tzitzira A, et al.
DNA methylation of tumor suppressor and metastasis suppressor genes in circulating tumor cells.
Clin Chem. 2011; 57(8):1169-77 [PubMed] Related Publications
BACKGROUND: Circulating tumor cells (CTCs) are associated with prognosis in a variety of human cancers and have been proposed as a liquid biopsy for follow-up examinations. We show that tumor suppressor and metastasis suppressor genes are epigenetically silenced in CTCs isolated from peripheral blood of breast cancer patients.
METHODS: We obtained peripheral blood from 56 patients with operable breast cancer, 27 patients with verified metastasis, and 23 healthy individuals. We tested DNA extracted from the EpCAM-positive immunomagnetically selected CTC fraction for the presence of methylated and unmethylated CST6, BRMS1, and SOX17 promoter sequences by methylation-specific PCR (MSP). All samples were checked for KRT19 (keratin 19, formerly CK-19) expression by reverse-transcription quantitative PCR.
RESULTS: In CTCs of patients with operable breast cancer, promoter methylation of CST6 was observed in 17.9%, BRMS1 in 32.1%, and SOX17 in 53.6% of patients. In CTCs of patients with verified metastasis, promoter methylation of CST6 was observed in 37.0%, BRMS1 in 44.4%, and SOX17 in 74.1%. In healthy individuals, promoter methylation of CST6 was observed in 4.3%, BRMS1 in 8.7%, and SOX17 in 4.3%. DNA methylation of these genes for both operable and metastatic breast cancer was significantly different from that of the control population.
CONCLUSIONS: DNA methylation of tumor suppressor and metastasis suppressor genes is a hallmark of CTCs and confirms their heterogeneity. Our findings add a new dimension to the molecular characterization of CTCs and may underlie the acquisition of malignant properties, including their stem-like phenotype.

Bodenstine TM, Vaidya KS, Ismail A, et al.
Homotypic gap junctional communication associated with metastasis suppression increases with PKA activity and is unaffected by PI3K inhibition.
Cancer Res. 2010; 70(23):10002-11 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Loss of gap junctional intercellular communication (GJIC) between cancer cells is a common characteristic of malignant transformation. This communication is mediated by connexin proteins that make up the functional units of gap junctions. Connexins are highly regulated at the protein level and phosphorylation events play a key role in their trafficking and degradation. The metastasis suppressor breast cancer metastasis suppressor 1 (BRMS1) upregulates GJIC and decreases phosphoinositide-3-kinase (PI3K) signaling. On the basis of these observations, we set out to determine whether there was a link between PI3K and GJIC in tumorigenic and metastatic cell lines. Treatment of cells with the well-known PI3K inhibitor LY294002, and its structural analogue LY303511, which does not inhibit PI3K, increased homotypic GJIC; however, we found the effect to be independent of PI3K/AKT inhibition. We show in multiple cancer cell lines of varying metastatic capability that GJIC can be restored without enforced expression of a connexin gene. In addition, while levels of connexin 43 remained unchanged, its relocalization from the cytosol to the plasma membrane was observed. Both LY294002 and LY303511 increased the activity of protein kinase A (PKA). Moreover, PKA blockade by the small molecule inhibitor H89 decreased the LY294002/LY303511-mediated increase in GJIC. Collectively, our findings show a connection between PKA activity and GJIC mediated by PI3K-independent mechanisms of LY294002 and LY303511. Manipulation of these signaling pathways could prove useful for antimetastatic therapy.

Li J, Li G
Cell cycle regulator ING4 is a suppressor of melanoma angiogenesis that is regulated by the metastasis suppressor BRMS1.
Cancer Res. 2010; 70(24):10445-53 [PubMed] Related Publications
ING4 has been previously shown to play important roles in regulating apoptosis, cell cycle progress, cell migration, and invasion. In this study, we investigated the impact of ING4 on melanoma angiogenesis. ING4 overexpression strongly suppressed the growth of human umbilical vein endothelial cells (HUVEC) and their ability to form tubular structure in vitro. We also found that ING4 inhibits interleukin-6 (IL-6) at both mRNA and protein levels through suppressing NF-κB activity. Knockdown of endogenous ING4 resulted in enhanced HUVEC growth and IL-6 expression. Our in vivo studies using nude mice confirmed that ING4 inhibited blood vessel formation and the recruitment of CD31-positive cells in matrigel plugs. Furthermore, we found that expression of ING4 was induced by BRMS1, a metastasis suppressor that inhibits melanoma angiogenesis through inhibiting NF-κB activity and IL-6 level as well. Further experiments showed that ING4 knockdown abrogated the suppressive effect of BRMS1 on HUVEC growth, whereas ING4 overexpression inhibited BRMS1 knockdown-induced angiogenesis, indicating that ING4 is a downstream target of BRMS1 in regulating tumor angiogenesis. Collectively, our findings indicate that ING4 is induced by BRMS1 and that it inhibits melanoma angiogenesis by suppressing NF-κB activity and IL-6 expression. Restoration of ING4 function offers a potential new strategy for the treatment of human melanoma.

Li J, Cheng Y, Tai D, et al.
Prognostic significance of BRMS1 expression in human melanoma and its role in tumor angiogenesis.
Oncogene. 2011; 30(8):896-906 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Breast cancer metastasis suppressor 1 (BRMS1) has been reported to suppress metastasis without significantly affecting tumorigenicity in breast cancer and ovarian cancer. To investigate the role of BRMS1 in human melanoma progression and prognosis, we established tissue microarray and BRMS1 expression was evaluated by immunohistochemistry in 41 dysplastic nevi, 90 primary melanomas and 47 melanoma metastases. We found that BRMS1 expression was significantly decreased in metastatic melanoma compared with primary melanoma or dysplastic nevi (P=0.021 and 0.001, respectively, χ(2) test). In addition, reduced BRMS1 staining was significantly correlated with American Joint Committee on Cancer stages (P=0.011, χ(2) test), but not associated with tumor thickness, tumor ulceration and other clinicopathological parameters. Furthermore, BRMS1 expression was significantly correlated with disease-specific 5-year survival of melanoma patients (P=0.007, log-rank test). Multivariate Cox regression analysis revealed that BRMS1 staining was an independent prognostic factor for melanoma patients (relative risk=0.51; confidence interval=0.29-0.91; P=0.022). Moreover, we demonstrated that BRMS1 overexpression inhibited endothelial cell growth and tube formation ability by suppressing NF-κB activity and IL-6 expression in vitro. We also showed that knockdown of BRMS1 increased IL-6 expression and promoted endothelial cell growth and tube formation. In addition, our data revealed that the BRMS1-mediated IL-6 expression is dependent on NF-κB. Strikingly, our in vivo studies using nude mice confirmed that BRMS1 inhibited blood vessel formation and the recruitment of CD31-positive cells in matrigel plugs. Taken together, BRMS1 expression was decreased in metastatic melanomas, which resulted in deficient suppression of angiogenesis and contributed to melanoma progression. BRMS1 may serve an important prognostic marker and therapeutic target for melanoma patients.

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