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Breast Cancer Metastasis Suppressor 1 Inhibits Gene Expression by Targeting Nuclear Factor-KB Activity

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Breast Cancer Metastasis Suppressor 1 Inhibits Gene Expression by Targeting Nuclear Factor-KB Activity Research Article Breast Cancer Metastasis Suppressor 1 Inhibits Gene Expression by Targeting Nuclear Factor-KB Activity Muzaffer Cicek,1 Ryuichi Fukuyama,1 Danny R. Welch,2 Nywana Sizemore,1 and Graham Casey1 1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio and 2Department of Pathology, Comprehensive Cancer Center, and National Foundation for Cancer Research Center for Metastasis Research, University of Alabama at Birmingham, Birmingham, Alabama Abstract An important component of metastatic dissemination is the Breast cancer metastasis suppressor 1 (BRMS1) functions as a proteolysis and degradation of the extracellular matrix (ECM), and metastasis suppressor gene in breast cancer and melanoma among the key mediators of ECM remodeling is the urokinase-type cell lines, but the mechanism of BRMS1 suppression remains plasminogen activator (uPA), a serine protease that stimulates the conversion of inactive plasminogen to the broad-spectrum unclear. We determined that BRMS1 expression was inversely correlated with that of urokinase-type plasminogen activator protease plasmin (4, 5). Plasmin mediates cellular invasion directly (uPA), a prometastatic gene that is regulated at least in part by by degrading members of the matrix proteins (6, 7) and indirectly nuclear factor-KB (NF-KB). To further investigate the role of by activating matrix metalloproteinases (MMP; ref. 8). Several NF-KB in BRMS1-regulated gene expression, we examined NF- groups have shown that uPA plays a critical role in tumor KB binding activity and found an inverse correlation between metastasis (9) and that elevated levels of uPA as well as its inhibitor BRMS1 expression and NF-KB binding activity in MDA-MB-231 plasminogen activator inhibitor-1 (PAI-1) are strong indicators of poor prognosis in breast cancers (10–14). breast cancer and C8161.9 melanoma cells stably expressing n n BRMS1. In contrast, BRMS1 expression had no effect on Recent studies have shown that the nuclear factor- B (NF- B) activation of the activator protein-1 transcription factor. transcription factor positively regulates uPA expression as well as several other genes implicated in angiogenesis and metastasis Further, we showed that suppression of both constitutive and n tumor necrosis factor-A–induced NF-KB activation by BRMS1 (15–17). NF- B is a heterodimeric transcription factor composed may be due to inhibition of IKBA phosphorylation and predominantly of p50 (NF-B1) and p65 (RelA) subunits and activation is regulated through interaction with the InBa kinase degradation. To examine the relationship between BRMS1 (IKK) complex (18–20). NF-nB is sequestered in the cytoplasm and uPA expression in primary breast tumors, we screened a n n breast cancer dot blot array of normalized cDNA from 50 through its interaction with inhibitors of NF- B(IB). Following certain stimuli, a cascade of events leads to the phosphorylation of breast tumors and corresponding normal breast tissues. There n n was a significant reduction in BRMS1 mRNA expression in I B by the IKK complex and subsequent degradation of I B breast tumors compared with matched normal breast tissues through ubiquitination. This in turn leads to the liberation of NF- nB and its translocation to the nucleus where it transactivates NF- (paired t test, P <<<<<0.0001) and a general inverse correlation n n with uPA gene expression (P <<<<<0.01). These results suggest that B-responsive genes (21–24). NF- B is constitutively activated in at least one of the underlying mechanisms of BRMS1- many cancers, and several studies suggest that it plays a critical dependent suppression of tumor metastasis includes inhibi- role in apoptosis, deregulation of cell growth, and propensity of tion of NF-KB activity and subsequent suppression of uPA tumors to metastasize (16, 17, 25–32). expression in breast cancer and melanoma cells. (Cancer Res The present study was done to determine mechanisms 2005; 65(9): 3586-95) underlying the suppression of metastasis by BRMS1 in human breast cancer and melanoma cells. We show that highly invasive MDA-MB-231 breast cancer and C8161.9 melanoma cell lines show Introduction constitutive NF-nB activity and that BRMS1 expression inversely Breast cancer metastasis suppressor 1 (BRMS1) is a known correlates with suppression of constitutive and tumor necrosis metastasis suppressor gene, and high expression of BRMS1 in factor-a (TNF-a)–induced activation of NF-nB-dependent uPA both breast cancer and melanoma cell lines significantly reduces gene expression. Furthermore, BRMS1 seems to suppress NF-nB their metastatic potential without affecting primary tumor activity by blocking InBa phosphorylation and degradation. growth (1). BRMS1 is a nuclear protein that contains an Finally, we show a general inverse correlation between BRMS1 imperfect leucine zipper motif and coiled-coiled domains (1), and uPA expression in primary breast tumors. These data suggest suggesting that it may function as part of a transcriptional that BRMS1 regulates metastatic potential at least in part through complex. Recent studies suggest that BRMS1 inhibits metastasis the down-regulation of NF-nB-dependent metastasis-related gene in part through gene regulation via interaction with histone expression. deacetylases (HDAC; refs. 2, 3). However, the underlying mechanism of BRMS1 metastasis gene regulation remains Materials and Methods unclear. Cell lines. The MDA-MB-231 estrogen receptor–negative human breast cancer cell line is highly metastatic to the lung when injected i.v. (33). The Requests for reprints: Graham Casey, Department of Cancer Biology, ND50, C8161 amelanotic human melanoma cell line is metastatic to the lung when Lerner Research Institute, Cleveland Clinic Lerner School of Medicine, 9500 Euclid injected s.c., i.d., or i.v. in nude mice (34). The C8161.9 is a highly metastatic Avenue, Cleveland, OH 44195. Phone: 216-445-9754; Fax: 216-445-0610; E-mail: [email protected]. clone obtained by limiting dilution cloning of parental C8161 cells (35). I2005 American Association for Cancer Research. MDA-MB-231 and C8161.9 cells were grown in DMEM (Life Technologies, Cancer Res 2005; 65: (9). May 1, 2005 3586 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2005 American Association for Cancer Research. BRMS1 Negatively Regulates NF-kB Grand Island, NY) supplemented with 5% FCS, 1% L-glutamine, and 1% instructions. RNA (15 Ag) was separated on 1.5% agarose gels containing j penicillin and streptomycin in 5% CO2 and 95% air at 37 C. All cultures 2.2 mol/L formaldehyde, transferred to nylon membranes (Nytran Super were tested and shown free of Mycoplasma contamination. MDA-MB-231 Charge, Schleicher & Schuell, Dassel, Germany), and UV cross-linked. cells were passaged at 80% to 90% confluence using a solution of 0.125% Probes for BRMS1 and uPA were amplified by PCR from MCF-7- and MDA- trypsin and 2 mmol/L EDTA in Ca2+/Mg2+-free DMEM. C8161.9 cells were MB-231-derived cDNA, respectively. PCR products were radiolabeled with passaged at 80% to 90% confluence using Ca2+/Mg2+-free PBS containing 2 [32P]dATP by random priming using a DNA labeling kit (Ambion Inc., mmol/L EDTA. Full-length BRMS1 cDNA was cloned into the mammalian Austin, TX). Northern blot hybridization was done using QuickHyb constitutive expression vector pcDNA3 (Invitrogen, San Diego, CA) and (Clontech Laboratories, Inc., Palo Alto, CA) following the manufacturer’s transfected stably into parental cells by electroporation (GenePulser, Bio- instructions. After hybridization, membranes were washed twice in 0.2% Rad, Hercules, CA; refs. 36, 37). Control cells were transfected with empty SSC (1Â SSC is 0.15 mol/L NaCl/0.015 mol/L sodium citrate) containing pcDNA vector. The vector control MDA-MB-231/pcDNA was a single 0.1% (w/v) SDS at room temperature for 1 hour and finally in 0.1% SSC/0.1% transfectant that was shown to retain a high metastatic phenotype SDS at 50jC for 45 minutes. Membranes were exposed overnight at À80jC equivalent to parental cells (1). The vector control C8161.9/pcDNA is a to Kodak BioMax film. RNA levels were quantified and normalized against pooled transfectant source shown to retain a highly metastatic phenotype 28S RNA for loading. similar to parental cells (37). Real-time PCR quantification. The following uPA primers were Electrophoretic mobility shift assay and nuclear factor-KB designed using Primer Express version 1.5 (Applied Biosystems, Foster City, activation. Electrophoretic mobility shift assay (EMSA) was done to CA): uPA (forward) 5V-GCCTTGCTGAAGATCCGTTC-3V and uPA (reverse) determine the effect of BRMS1 expression on NF-nB activation (38). Briefly, 5V-GGATCGTTATACATCGAGGGGCA-3V. A single PCR-amplified band was nuclear and cytoplasmic proteins were extracted from exponentially observed on ethidium-stained gels using standard PCR conditions. Real- growing cells, and protein concentration was quantified using BCA protein time PCR experiments were done using the SYBR Green PCR Core kit assay (Pierce, Rockford, IL). Nuclear proteins (10 Ag) were incubated at (Applied Biosystems) according to the vendor’s instructions and an ABI room temperature for 20 minutes with 32P-end-labeled nucleotide derived 7900HT (Applied Biosystems) real-time PCR instrument. uPA expression from a NF-nB binding sequence (5V-AGTTGAGGGGACTTTCCCAGG-3V) levels were calibrated using endogenous glyceraldehyde-3-phosphate from the immunoglobulin gene promoter (38) and the activator protein-1 dehydrogenase (GAPDH) expression levels as an internal control. The (AP-1) transcription factor consensus oligonucleotide (5V-CGCTTGATGAGT- following GAPDH primers were designed using Primer Express version 1.5: CAGCCGGAA-3V; Promega, Madison, WI). For TNF-a–dependent NF-nB GAPDH (forward) 5V-GAAGGTGAAGGTCGCAGT-3V and GAPDH (reverse) activation, exponentially growing cells were rinsed twice with 1Â PBS and 5V-GAAGATGGTGATGGGATTTC-3V. Cycle conditions were 95jC for 10 treated with TNF-a (20 ng/mL) in serum-free DMEM for various times (0-2 minutes (AmpliTaq Gold activation) followed by 45 cycles of 95jC for 15 hours).
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