Note | 1-246 amino acids Coiled-Coil Motifs: 51-81 and 147-180 amino acids Imperfect Leucine Zippers: 67-88, 131-152, 138-159, 153-174 and 160-181 amino acids Nuclear Localisation Signals: 198-205, 239-245 amino acids cAMP/cGMP Phosphorylation Sites: 55-58 and 240-243 amino acids |
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| Schematic representation of the BRMS1 protein. The coiled coil motifs are shown in yellow, nuclear localisation signals are shown in blue, the imperfect leucine zipper motifs are shown in green and the cAMP/cGMP phosphorylation sites are shown in purple. |
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Description | The BRMS1 protein consists of 246 amino acids, two coiled-coil motifs and a number of imperfect leucine zipper motifs at amino acids 67-88, 131-152, 138-159, 153-174 and 160-181, respectively. Several putative phosphorylation sites have also been identified (see diagram above) (Seraj et al., 2000). The full length protein is 2.8 kDa. In addition, a novel BRMS1-homologue protein (p40) has been identified, which may play a role in transcription repression by recruiting histone deacetylase complexes (Nikolaev et al., 2004). |
Expression | BRMS1 was originally identified by differential display analysis. Transfection of BRMS1 cDNA into MDA-MB-435 and MDA-MB-231 breast cancer cell lines was shown to suppress formation of metastasis without affecting tumourigenicity (Samantet al., 2000). BRMS1 overexpression also inhibits lung and lymph node metastasis in experimental melanoma and ovarian cancer models (Shevde et al., 2002; Zhang et al., 2006). Reduced expression of BRMS1 has been correlated with poor prognosis in human breast cancer (Zhang et al., 2006). In addition, reduced expression of BRMS1 has been observed in breast cancer brain metastasis (Stark et al., 2005). |
Localisation | The BRMS1 protein is predominantly located in the nucleus. |
Function | Breast cancer metastasis suppressor gene 1 is a member of a growing family of metastasis suppressor genes which prevent the development of metastasis without affecting tumour growth (Welch et al., 2000). The main cause of mortality in cancer patients is the formation of metastasis, a multistep process, modulated largely by activators and suppressors of metastasis (Chambers et al., 2002; Duffy, 1996). BRMS1 has been shown to suppress metastasis of human breast cancer and melanoma cells in nude mice (Seraj et al., 2000; Samant et al., 2000; Samant et al., 2002). It maps to chromosome 11, a region of the genome which has been implicated in the progression and metastasis of human breast cancer (Seraj et al., 2000). Recent studies suggest that BRMS1 inhibits metastasis through an interaction with histone deacetylase complexes, resulting in aberrant gene regulation (Hurst et al., 2006; Samant et al., 2007). It is a selective component of the mSin3a/histone deacetylase corepressor complex and when activated results in basal transcriptional repression (Meehan et al., 2004). In addition, BRMS1 has been shown to negatively regulate NF-kB activity, which is constitutively activated in many human cancers and plays an important role in apoptosis (Samant et al., 2007). Metge et al. (2008) recently identified two hypermethylated CpG islands in the BRMS1 promoter . This group also observed reduced expression of BRMS1 in metastatic breast cancer cell lines. They hypothesized that promoter hypermethylation may be involved in this downregulation of BRMS1 expression (Metge et al., 2008). Methylation appears to be an important early event in the etiology of human breast cancer, resulting in the silencing of many tumour suppressor genes, including BRMS1 (Nephew et al., 2003). Metge et al. (2008) suggest that epigenetic silencing of BRMS1 may be an important prognostic indicator in human breast cancer . Other functions of BRMS1 include restoring homotypic gap junctional intercellular communications (Samant et al., 2000; Shevde et al., 2002; Saunders et al., 2001), inhibiting expression of the metastasis-promoting chemokine osteopontin (Samant et al., 2007; DeWald et al., 2005). Furthermore, BRMS1 has been shown to play a role in phosphoinositide signaling. |
Dissemination and growth of cancer cells in metastatic sites |
Chambers AF, Groom AC, MacDonald IC. |
Nat Rev Cancer. 2002 Aug;2(8):563-72. |
PMID 12154349 |
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Breast cancer metastasis suppressor 1 inhibits gene expression by targeting nuclear factor-kappaB activity |
Cicek M, Fukuyama R, Welch DR, Sizemore N, Casey G. |
Cancer Res. 2005 May 1;65(9):3586-95. |
PMID 15867352 |
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Metastasis suppression by breast cancer metastasis suppressor 1 involves reduction of phosphoinositide signaling in MDA-MB-435 breast carcinoma cells. |
DeWald DB, Torabinejad J, Samant RS, Johnston D, Erin N, Shope JC, Xie Y, Welch DR. |
Cancer Res. 2005 Feb 1;65(3):713-7. |
PMID 15705865 |
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Urokinase-plasminogen activator, a marker for aggressive breast carcinomas. Preliminary report. |
Duffy MJ, O'Grady P, Devaney D, O'Siorain L, Fennelly JJ, Lijnen HJ. |
Cancer. 1988 Aug 1;62(3):531-3. |
PMID 3134120 |
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Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. |
Duffy MJ, Reilly D, O'Sullivan C, O'Higgins N, Fennelly JJ, Andreasen P. |
Cancer Res. 1990 Nov 1;50(21):6827-9.Click here to read |
PMID 2119883 |
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The biochemistry of metastasis. |
Duffy MJ. |
Adv Clin Chem. 1996;32:135-66. (Review) |
PMID 8899072 |
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Loss of breast cancer metastasis suppressor 1 protein expression predicts reduced disease-free survival in subsets of breast cancer patients. |
Hicks DG, Yoder BJ, Short S, Tarr S, Prescott N, Crowe JP, Dawson AE, Budd GT, Sizemore S, Cicek M, Choueiri TK, Tubbs RR, Gaile D, Nowak N, Accavitti-Loper MA, Frost AR, Welch DR, Casey G. |
Clin Cancer Res. 2006 Nov 15;12(22):6702-8. |
PMID 17121889 |
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Breast cancer metastasis suppressor 1 (BRMS1) is stabilized by the Hsp90 chaperone. |
Hurst DR, Mehta A, Moore BP, Phadke PA, Meehan WJ, Accavitti MA, Shevde LA, Hopper JE, Xie Y, Welch DR, Samant RS. |
Biochem Biophys Res Commun. 2006 Oct 6;348(4):1429-35. Epub 2006 Aug 10. |
PMID 16919237 |
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Expression of the breast cancer metastasis suppressor gene, BRMS1, in human breast carcinoma: lack of correlation with metastasis to axillary lymph nodes. |
Kelly LM, Buggy Y, Hill A, O'Donovan N, Duggan C, McDermott EW, O'Higgins NJ, Young L, Duffy MJ. |
Tumour Biol. 2005 Jul-Aug;26(4):213-6. Epub 2005 Jul 6. |
PMID 16006775 |
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Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. |
Look MP, van Putten WL, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Ferno M, Eppenberger-Castori S, Sweep CG, Ulm K, Peyrat JP, Martin PM, Magdelenat H, Brunner N, Duggan C, Lisboa BW, Bendahl PO, Quillien V, Daver A, Ricolleau G, Meijer-van Gelder ME, Manders P, Fiets WE, Blankenstein MA, Broet P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex LV, Klijn JG, O'Higgins N, Eppenberger U, Janicke F, Schmitt M, Foekens JA. |
J Natl Cancer Inst. 2002 Jan 16;94(2):116-28. |
PMID 11792750 |
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Breast cancer metastasis suppressor 1 (BRMS1) forms complexes with retinoblastoma-binding protein 1 (RBP1) and the mSin3 histone deacetylase complex and represses transcription. |
Meehan WJ, Samant RS, Hopper JE, Carrozza MJ, Shevde LA, Workman JL, Eckert KA, Verderame MF, Welch DR. |
J Biol Chem. 2004 Jan 9;279(2):1562-9. Epub 2003 Oct 26. |
PMID 14581478 |
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Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer. |
Metge BJ, Frost AR, King JA, Dyess DL, Welch DR, Samant RS, Shevde LA. |
Clin Exp Metastasis. 2008;25(7):753-63. Epub 2008 Jun 20. |
PMID 18566899 |
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Epigenetic gene silencing in cancer initiation and progression. |
Nephew KP, Huang TH. |
Cancer Lett. 2003 Feb 20;190(2):125-33. |
PMID 12565166 |
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The prognostic value of the soluble urokinase-type plasminogen activator receptor (s-uPAR) in plasma of breast cancer patients with and without metastatic disease. |
Nijziel MR, Van Oerle R, Hellenbrand D, Van Pampus EC, Hillen HF, Hamulyak K. |
J Thromb Haemost. 2003 May;1(5):982-6. |
PMID 12871365 |
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Identification of a novel BRMS1-homologue protein p40 as a component of the mSin3A/p33(ING1b)/HDAC1 deacetylase complex. |
Nikolaev AY, Papanikolaou NA, Li M, Qin J, Gu W. |
Biochem Biophys Res Commun. 2004 Oct 29;323(4):1216-22. |
PMID 15451426 |
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Breast cancer metastasis suppressor 1 (BRMS1) inhibits osteopontin transcription by abrogating NF-kappaB activation. |
Samant RS, Clark DW, Fillmore RA, Cicek M, Metge BJ, Chandramouli KH, Chambers AF, Casey G, Welch DR, Shevde LA. |
Mol Cancer. 2007 Jan 16;6:6. |
PMID 17227585 |
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Suppression of murine mammary carcinoma metastasis by the murine ortholog of breast cancer metastasis suppressor 1 (Brms1). |
Samant RS, Debies MT, Hurst DR, Moore BP, Shevde LA, Welch DR. |
Cancer Lett. 2006 Apr 28;235(2):260-5. Epub 2005 Jun 22. |
PMID 15978719 |
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Analysis of mechanisms underlying BRMS1 suppression of metastasis. |
Samant RS, Seraj MJ, Saunders MM, Sakamaki TS, Shevde LA, Harms JF, Leonard TO, Goldberg SF, Budgeon L, Meehan WJ, Winter CR, Christensen ND, Verderame MF, Donahue HJ, Welch DR. |
Clin Exp Metastasis. 2000;18(8):683-93. |
PMID 11827072 |
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Breast cancer metastatic potential correlates with a breakdown in homospecific and heterospecific gap junctional intercellular communication. |
Saunders MM, Seraj MJ, Li Z, Zhou Z, Winter CR, Welch DR, Donahue HJ. |
Cancer Res. 2001 Mar 1;61(5):1765-7. |
PMID 11280719 |
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Functional evidence for a novel human breast carcinoma metastasis suppressor, BRMS1, encoded at chromosome 11q13. |
Seraj MJ, Samant RS, Verderame MF, Welch DR. |
Cancer Res. 2000 Jun 1;60(11):2764-9. |
PMID 10850410 |
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Suppression of human melanoma metastasis by the metastasis suppressor gene, BRMS1. |
Shevde LA, Samant RS, Goldberg SF, Sikaneta T, Alessandrini A, Donahue HJ, Mauger DT, Welch DR. |
Exp Cell Res. 2002 Feb 15;273(2):229-39. |
PMID 11822878 |
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Reduced metastasis-suppressor gene mRNA-expression in breast cancer brain metastases. |
Stark AM, Tongers K, Maass N, Mehdorn HM, Held-Feindt J. |
J Cancer Res Clin Oncol. 2005 Mar;131(3):191-8. Epub 2004 Dec 8. |
PMID 15592684 |
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Molecular biology of breast cancer metastasis. Genetic regulation of human breast carcinoma metastasis. |
Welch DR, Steeg PS, Rinker-Schaeffer CW. |
Breast Cancer Res. 2000;2(6):408-16. Epub 2000 Jul 21. |
PMID 11250734 |
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Suppression of human ovarian carcinoma metastasis by the metastasis-suppressor gene, BRMS1. |
Zhang S, Lin QD, DI W. |
Int J Gynecol Cancer. 2006 Mar-Apr;16(2):522-31. |
PMID 16681721 |
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Reduced expression of the breast cancer metastasis suppressor 1 mRNA is correlated with poor progress in breast cancer. |
Zhang Z, Yamashita H, Toyama T, Yamamoto Y, Kawasoe T, Iwase H. |
Clin Cancer Res. 2006 Nov 1;12(21):6410-4. |
PMID 17085653 |
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