Breast Cancer Metastasis Suppressor Gene Research Articles

Breast cancer metastasis suppressor gene, breast cancer metastasis suppressor 1, may be associated with clinicopathological features of breast cancer.

We aim to investigate whether the breast cancer metastasis suppressor gene, breast cancer metastasis suppressor 1 (BRMS1), is correlated with clinicopathological features of breast cancer or not. Following a stringent inclusion and exclusion criteria, case-control studies related to the association between BRMS1 and breast cancer were selected from articles retrieved by electronic database searches. All statistical analyses were performed by Stata version 12.0 (Stata Corp, College Station, TX, USA). A total of 12 studies were ultimately included in this meta-analysis. Results of our meta-analysis suggested that BRMS1 protein in breast cancer tissues was significantly lower compared with normal breast tissues (odds ratio [OR] =0.08, 95% confidence interval [CI] =0.04-0.15, P < 0.001). The BRMS1 protein in metastatic breast cancer tissue was lower than that in nonmetastatic breast cancer tissue (OR = 0.20, 95% CI = 0.13-0.29, P < 0.001), and BRMS1 protein in tumor-node-metastasis (TNM) stages 1, 2 was found to be higher than TNM stages 3, 4 (OR = 4.62, 95% CI = 2.77-7.70, P < 0.001). With respect to breast cancer types, BRMS1 protein in all the three major types of breast cancer was lower than the normal tissues. We also found strong correlations between BRMS1 mRNA levels and TNM stage and tumor size. Our meta-analysis results showed that reduced BRMS1 expression level was significantly associated with clinicopathological features of breast cancer, suggesting that loss of expression or reduced levels of BRMS1 might be a strong indicator of the metastatic capacity of breast cancer, with poor prognosis.

DNA methylation modification of BRMS1 in triple-negative breast cancer and its correlation with tumor metastasis

Objective: To investigate the effect of methylation status of breast cancer metastasis suppressor gene 1 (BRMS1) on the expression of breast cancer and the biological behavior of cancer cells in triple-negative breast cancer (TNBC). Methods: The expression of BRMS1 in TNBC tissues and corresponding non-malignant tissues and its relationship with clinicopathological parameters were detected by immunohistochemistry. The mRNA and protein expression of BRMS1 in normal breast epithelial cells and TNBC cells were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The methylation specific polymerase chain reaction (MSP) was used to detect the methylation status of BRMS1 in each cell. These cells were treated with demethylated preparations (5-Aza-dC) to re-activate BRMS1 expression. Using tumor cell invasion assay to detect influence of BRMS1 demethylation on the invasion capacity of cancer cells. The data were statistically analyzed. Results: The positive expression rate of BRMS1 protein in TNBC tissues was significantly lower than that in corresponding non-malignant tissues (χ(2)= 6.635, P<0.05). The mRNA expression level of BRMS1 in patients with lymph node metastasis was significantly lower than those with no lymph node metastasis (P=0.018). The down-regulation of BRMS1 expression was related to the methylation of DNA promoter, which was statistically significant (χ(2)=14.68, P<0.05). The mRNA and protein expression of BRMS1 was also correlated with tumor size and TNM staging (P=0.000-0.003). After using 5-Aza-dC, the number of cells with invasive capacity was significantly lower than those of the control group (t=3.262-10.72, P<0.05). Conclusions: The decrease of BRMS1 expression in TNBC cells is related to the methylation of DNA. Demethylation can inhibit the invasion of breast cancer cells.

Mechanism of breast cancer metastasis suppressor gene 1 inhibiting tumor metastasis

Breast cancer metastasis suppressor gene 1(BRMS1) significantly reduces the invasion and metastasis of cancer cells. BRMS1 gene expression is decreased or deleted in the cells of various malignant tumors. BRMS1 gene can inhibit tumor cells invasion and metastasis by means of regulating gene transcription and protein translation by phosphoinositide signaling and nuclear factor-κB (NF-κB) signaling pathways, repairing intercellular communication and interacting with the mSin3-histone deacetylase (HDAC) complex, estrogen receptor and other proteins. BRMS1 gene may be a new target for the gene treatment of tumor metastasis. Key words: Gene, neoplasm; Tumor metastasis; Breast cancer metastasis suppressor gene 1; Inhibiting effect

Effect of BRMS1 on tumorigenicity and metastasis of human rectal cancer.

Breast cancer metastasis suppressor gene-1 (BRMS1) is newly discovered tumor metastasis gene, which has been reported to play an important role in the progression of human tumor. However, its role in rectal cancer has never been investigated. In this present study, we evaluated the associated of BRMS1 with colorectal cancer, its value in prognosis, and its role in metastasis of rectal cancer. BRMS1 expression examined in 80 patients and the role of BRMS1 in metastasis was studied using mice model. Our results showed that BRMS1 expression was significantly associated with clinicopathological parameters in rectal cancer patients and overexpression of BRMS1 in rectal cancer xenograft led to decreased growth, invasiveness and metastasis. Our findings indicate that high expression of BRSM1 in rectal cancer plays an essential role in tumor progression.

Pharmacological Levels of Withaferin A (Withania somnifera) Trigger Clinically Relevant Anticancer Effects Specific to Triple Negative Breast Cancer Cells

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.

The Drosophila ortholog of breast cancer metastasis suppressor gene, dBrms1, is critical for developmental timing through regulating ecdysone signaling

BRMS1 was first discovered as a human breast carcinoma metastasis suppressor gene. However, the mechanism of BRMS1 in tumor metastasis and its developmental role remain unclear. In this paper, we first report the identification of the Drosophila ortholog of human BRMS1, dBrms1. Through a genetic approach, the role of dBrms1 during development has been investigated. We found that dBrms1 is an essential gene and loss of dBrms1 function results in lethality at early developmental stages. dBrms1mutants displayed phenotypes such as developmental delay and failure to initiate metamorphosis. Further analysis suggests that these phenotypes are contributed by defective ecdysone signaling and expression of target genes of the ecdysone pathway. Therefore, dBrms1 is required for growth control by acting as a modulator of ecdysone signaling in Drosophila and is required for metamorphosis for normal development.

Abstract 3425: Prognostic significance of BRMS1 promoter methylation in operable breast cancer

Abstract Backround: Breast Cancer Metastasis Suppressor gene-1 (BRMS1) suppresses breast cancer metastasis in multiple experimental models by reducing solitary cell survival and inhibiting growth initiation. Loss of BRMS1 expression has been shown to predict reduced disease-free survival in subsets of breast cancer patients. The BRMS1 promoter region contains a promoter-associated CpG island (CGI) that encompasses the transcriptional start site.The aim of our study was to investigate the methylation status of BRMS1 in breast tumors (FFPES) of operable breast cancer patients and evaluate its prognostic significance. Patients and methods: Using methylation-specific PCR (MSP), we examined BRMS1 promoter methylation in 116 fixed paraffin-embedded tissues (FFPEs): 5 pairs of breast tumors and their surrounding non-cancerous tissues, 4 non-cancerous tissues, 10 benign breast tumors (fibroadenomas), 10 normal breast tissues and 82 breast tumors. All breast tumors were isolated from patients with operable breast cancer. Results: Methylation of BRMS1 promoter was observed in 0/19 (0%) noncancerous breast tissues, in 0/10 (0%) benign breast tumors (fibroadenomas) and in 31/82 (37.8 %) breast cancer tumors. During the follow-up period 22/82 (26.8%) patients relapsed and 20 (24.4%) patients died. BRMS1 methylation was detected in 13/22 (59.1%) patients that relapsed and in 12/20 (60.0%) of patients who died. Disease-free interval (DFI) and overall survival (OS) were significantly associated with BRMS1 promoter methylation (P=0.007). Conclusion: We show for the first time that BRMS1 promoter methylation status in FFPEs from operable breast cancer patients provides important prognostic information and merits to be further evaluated and validated in a larger cohort of patients. This finding is consistent with other studies that showed significant down-regulation of BRMS1 in some breast tumors, especially in metastatic disease, because of epigenetic silencing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3425. doi:1538-7445.AM2012-3425

BRMS1 transcriptional repression correlates with CpG island methylation and advanced pathological stage in non‐small cell lung cancer

Breast cancer metastasis suppressor gene-1 (BRMS1) mRNA and protein expression are significantly decreased in non-small cell lung cancer (NSCLC) and this is a poor prognostic indicator. Given that the BRMS1 promoter region contains a promoter-associated CpG island (CGI) that encompasses the transcriptional start site, we hypothesized that decreased BRMS1 mRNA and protein levels in NSCLC was secondary to increased BRMS1 promoter methylation. Methylation-specific PCR (MSP) of the two known CGIs (-3477 to - 2214 and - 531 to + 608) in the BRMS1 genome was performed in NSCLC cells. This demonstrated a robust increase in methylation of the promoter-associated CGI (-531 to + 608) but not of the upstream CGI (-3477 to - 2214). To experimentally verify that methylation contributes to BRMS1 transcriptional repression, we cloned the BRMS1 promoter region, including the promoter-associated CGI, into a luciferase reporter gene and found that BRMS1 promoter activity was dramatically inhibited under methylated conditions. We then assessed the BRMS1 methylation profile with MSP and bisulphite-sequencing PCR in human NSCLC adenocarcinoma (n = 20) and squamous cell carcinoma (n = 20) relative to adjacent non-cancerous bronchial epithelium. There was a significant increase in BRMS1 promoter methylation in all NSCLC specimens relative to non-cancerous tissues, with the most dramatic difference in squamous cell cancer histology. Subsequent immunostaining demonstrated that nuclear BRMS1 expression is reduced in lung cancer specimens compared to normal bronchial epithelium. The association between BRMS1 promoter methylation and specific clinical and histopathological variables was examined using a general linear model. Pathological tumour stage was associated with increased BRMS1 methylation in squamous cell cancers. These observations demonstrate that methylation of the promoter-associated CGI in BRMS1 results in its transcriptional repression, and highlight the potential clinical relevance of this methylation event with respect to NSCLC tumour histology and pathological stage.

Abstract LB-278: BRMS1 promoter methylation correlates with decreased expression of BRMS1 in non-small cell lung cancer

Abstract Background: Breast cancer metastasis suppressor gene-1 (BRMS1) mRNA and protein expression are significantly decreased in non-small cell lung cancer (NSCLC) cell lines and human NSCLC when compared to normal bronchial epithelial cells and adjacent noncancerous tumor tissue, respectively. We hypothesized that one mechanism through which BRMS1 expression was decreased in NSCLC was through BRMS1 promoter methylation. Materials and Methods: Human NSCLC BRMS1 promoter methylation was evaluated using methylation-specific PCR and bisulfite sequencing. The effect of methylation on BRMS1 mRNA and protein expression was assessed following treatment with 5-azacitidine, a demethylating agent in NSCLC cell lines. BRMS1 transcriptional activity was assessed using a human BRMS1-luc reporter gene construct cloned by our group. Student's T-Test and Chi-square tests were used to determine significance between variables of two patient populations separated based on tumor histology (squamous cell or adenocarcinoma) and to evaluate the methylation profile between the two tumor histologies. Immunohistochemical analysis for BRMS1 protein was performed on both tumor and adjacent noncancerous bronchial epithelium. A general linear model tested the association between BRMS1 promoter methylation in human NSCLC and specific clinical and histopathologic variables. Results: The BRMS1 promoter region contains a CpG island that was hypermethylated in all NSCLC cell lines and human tumors. This strongly correlated with reduced BRMS1 promoter activity. NSCLC cell lines treated with 5-azacitidine showed a robust recovery of BRMS1 mRNA and protein levels, suggesting that promoter methylation is involved in BRMS1 transcriptional regulation. Analysis of 40 patient NSCLC samples (20 adenocarcinoma and 20 squamous cell) identified a significant increase in the amount of BRMS1 promoter methylation when comparing tumor specimen to adjacent noncancerous tissue for both tumor histologies (p&amp;lt;0.0001). Additionally, the BRMS1 promoter region was significantly more methylated in squamous cell compared to adenocarcinoma histology (p=0.01). Subsequent immunohistochemical analysis confirmed a correlation between BRMS1 promoter methylation and decreased bronchial epithelium BRMS1 protein expression (p=0.06). Moreover, in the squamous cell histology, pathologic tumor stage was associated with elevated BRMS1 methylation (p=0.04). Conclusions: These studies identify BRMS1 promoter methylation as an important mechanism for silencing BRMS1 expression in NSCLC and highlight the potential clinical relevance of this epigenetic signature with respect to tumor histology and stage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-278.

Expression of the Breast Cancer Metastasis Suppressor Gene, BRMS1, in Human Breast Carcinoma: Lack of Correlation with Metastasis to Axillary Lymph Nodes

The BRMS1 (breast cancer metastasis suppressor 1) gene has been found to suppress metastasis in animal models without inhibiting primary tumor growth. The aim of this study was to measure expression of BRMS1 mRNA in a panel of human breast carcinomas and compare its expression with parameters of local dissemination such as tumor size and lymph node metastasis. We also compared expression of BRMS1 mRNA in normal breast tissue, fibroadenomas, primary breast cancers and axillary nodal metastases from primary breast cancers. BRMS1 mRNA was detected in 10/11 (90%) specimens of normal breast tissue, 12/16 (75%) fibroadenomas, 64/82 (78%) primary breast cancer and 11/15 (64%) lymph node metastases (p, NS). In the primary cancer, expression was independent of tumor size, tumor grade, metastasis to axillary nodes and hormone receptor status. Furthermore, similar levels of BRMS1 were found in normal breast tissue, primary breast carcinomas and lymph node metastases from primary breast cancer. Our results do not suggest a role for BRMS1 in suppressing metastasis to local lymph nodes in patients with breast cancer.

Comparative sequence analysis in eight inbred strains of the metastasis modifier QTL candidate gene Brms1.

Comparative sequence analysis in eight inbred strains of the metastasis modifier QTL candidate gene Brms1.