Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis and correlates with improved patient survival in non-small cell lung cancer

Abstract

Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. The role of BRMS1 in non-small cell lung cancer (NSCLC) is not well established. To assess in vitro and in vivo metastatic behavior H1299 NSCLC cells stably expressing BRMS1 or a vector control were created. BRMS1 expression significantly decreases both migration and invasion of NSCLC cells in vitro. Importantly, in flank xenografts, BRMS1 suppresses the formation of pulmonary and hepatic metastases but does not significantly affect primary tumor growth. To evaluate whether BRMS1 is related to the progression of NSCLC, we examined BRMS1 expression in human NSCLC. Both BRMS1 mRNA and protein levels are diminished in NSCLC compared to adjacent non-cancerous lung. BRMS1 expression is also lower in squamous cell carcinoma compared to adenocarcinoma. Moreover, preservation of tumor BRMS1 expression is associated with improved patient survival. Thus, BRMS1 functions as a metastasis suppressor and may be a prognostic indicator for human NSCLC.

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

“…Of these tumor samples, 5 had lymph node metastasis, and 5 did not. Consistent with our previous findings (18,25), BRMS1 was downregulated in all 10 tested NSCLC samples compared with levels in adjacent tissue (Fig. 7A).…”

“…The breast cancer metastasis suppressor 1 gene (BRMS1) is a metastasis suppressor gene that significantly reduces intratumoral expression in NSCLC, compared with that in adjacent tissue (17,18). Importantly, we have shown that the reduction of BRMS1 expression at protein and mRNA levels significantly correlates with NSCLC progression and poor prognosis (18).…”

“…Importantly, we have shown that the reduction of BRMS1 expression at protein and mRNA levels significantly correlates with NSCLC progression and poor prognosis (18). 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).…”

“…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).…”

“…Transwell invasion assays. Cell invasion was assessed as previously described (18). In brief, the chambers were precoated with type IV collagen (0.25 mg/ml) in 0.25% acetic acid overnight, and a 2.5 ϫ 10 4 -cell suspension was plated into the chamber.…”