BRMS1 (breast cancer metastasis suppressor 1)

	Exon-Intron structure of human BRMS1.
Description	BRMS1 is a functioning gene comprising 10 exons and spanning 7.8 kb of genomic DNA. Alternative splicing results in two mRNA transcripts, translating into two distinct proteins, 246 amino acids and 290 amino acids in length, respectively (Seraj et al., 2000). The longer transcript uses an alternative splice site in the 3' untranslated terminal exon which results in the use of a downstream stop codon. The encoded protein has a longer distinct C-terminus.
Transcription	Structural analysis of the BRMS1 promoter has revealed the presence of two hypermethylated cytosine-phosphoguanine (CpG) islands (Metge et al., 2008). Hypermethylation of CpG islands restricts the activity of the BRMS1 protein, mainly due the tightly packed nucleosomes (Metge et al., 2008). Gene expression can also be suppressed by blocking transcription factor binding.

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
	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.
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.

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