Suppression of human ovarian carcinoma metastasis by the metastasis-suppressor gene, BRMS1

Abstract

Metastasis-suppressor genes, by definition, suppress metastasis without affecting tumorigenicity and, hence, present attractive targets as prognostic or therapeutic markers. BRMS1 (breast cancer metastasis suppressor) has recently been identified as a metastasis-suppressor gene for human breast cancer and melanoma. Expression of BRMS1 messenger RNA (mRNA) in multitissue including normal prostate, ovarian, testis, and colon has been detected by northern blot analysis. We hypothesize that the role of BRMS1 in tumor progression may not be limited to breast cancer and melanoma. We previously found that BRMS1 mRNA levels in primary ovarian epithelial carcinomas were significantly lower than that in normal ovarian and benign tumors (P < 0.05), and statistical analysis of BRMS1 mRNA levels revealed that BRMS1 mRNA levels were significantly higher in early tumor stages (I, II) compared with advanced tumor stages (III, IV) in which lymph node or distant metastases were present (P < 0.01). Our data showed that reduced BRMS1 mRNA seems to influence ovarian carcinoma metastatic ability. Therefore, we transfected BRMS1 plasmid into highly malignant ovarian carcinoma cell line, HO-8910PM, and examined cell biologic behaviors including proliferation, adhesion, invasion, and metastasis in vitro and in vivo. BRMS1 expression did not alter the proliferation of HO-8910PM cells in vitro and primary tumor formation in vivo. But, BRMS1 expression significantly suppressed the cell adhesion to extracellular matrix components and in vitro cell invasion in BRMS1-transfected HO-8910PM cells compared to parental HO-8910PM and vector-only transfectants (HO-8910PM-vect). Furthermore, motility of BRMS1 transfectants was inhibited. lung colony formation of intravenously injected BRMS1 transfectants in nude mice was significantly reduced. Also, BRMS1 transfectants form significantly less metastatic to organs of peritoneal cavity in orthotopically implanted ovarian tumor nude models. We further discovered that BRMS1 expression did downregulate expression of an actin-bundling protein associated with cell motility -fascin, which perhaps is the mechanism underlying BRMS1 suppression of metastasis. These data suggested that in addition to its already described role in breast cancer and melanoma, BRMS1 functions as a metastasis-suppressor gene in ovarian carcinoma by modifying several metastatic-associated phenotypes, offering a new target for therapeutic intervention.

Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application

“…The Brms1 metastasis suppressor protein (67,68) has been functionally associated with the modulation of phospholipid metabolism. Specifically, Brms1-expressing cells showed significant decreases in endogenous levels of PIP 2 (i.e., <10% of controls).…”

Elevated Osteopontin Levels in Metastatic Melanoma Correlate with Epigenetic Silencing of Breast Cancer Metastasis Suppressor 1

“…Further studies have since shown that BRMS1 is not only a metastasis suppressor gene in breast cancer models but also in various other cancers such as melanoma and ovarian cancer [7,8,9]. Recent studies have also demonstrated that low levels of BRMS1 protein correlated with poor prognosis in cancer patients with advanced disease [10,11,12].…”

Loss of BRMS1 Promotes a Mesenchymal Phenotype through NF-κB-Dependent Regulation of Twist1

“…We recently showed, in both NSCLC cell lines and human specimens, that the reduction of BRMS1 in NSCLC is secondary to RelA/p65-mediated methylation of the BRMS1 promoter (19,20). The importance of BRMS1 in suppressing metastases has been demonstrated in melanoma, breast, hepatocellular, and ovarian carcinomas (18,(21)(22)(23)(24). BRMS1 has been shown to function as a corepressor to inhibit NF-B transactivation through deacetylation of the RelA/ p65 subunit at K310 (25).…”