{"gene":"BRMS1","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":2000,"finding":"BRMS1 was identified as a metastasis suppressor gene encoded at chromosome 11q13.1-q13.2; stable transfection into MDA-MB-435 and MDA-MB-231 breast carcinoma cells suppressed metastasis to lungs and regional lymph nodes without inhibiting primary tumor formation.","method":"Differential display, stable transfection, in vivo xenograft metastasis assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — replicated in two cell lines with in vivo functional readout; foundational paper with 233 citations","pmids":["10850410"],"is_preprint":false},{"year":2000,"finding":"BRMS1 expression restored homotypic gap junctional intercellular communication (GJIC) in human breast carcinoma cells and modestly inhibited cell motility, without affecting adhesion to ECM components, MMP expression, or other known metastasis suppressors.","method":"In vitro functional assays (GJIC, motility, adhesion, soft agar, MMP expression)","journal":"Clinical & experimental metastasis","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vitro assays in two cell lines, single lab","pmids":["11827072"],"is_preprint":false},{"year":2003,"finding":"BRMS1 interacts with retinoblastoma-binding protein 1 (RBP1) and at least seven members of the mSin3 histone deacetylase (HDAC) complex, co-immunoprecipitates enzymatically active HDAC proteins, and represses transcription when recruited to a Gal4 promoter; BRMS1 exists in large ~1.4–1.9 MDa mSin3 complexes and also smaller complexes with HDAC1; C-terminal 42 amino acids are not critical for mSin3 interaction.","method":"Yeast two-hybrid, co-immunoprecipitation, in vivo transcription repression assay, deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — yeast two-hybrid confirmed by reciprocal Co-IP, enzymatic activity measured, functional transcriptional repression assay with deletion mapping; 141 citations","pmids":["14581478"],"is_preprint":false},{"year":2004,"finding":"A BRMS1-homologous protein p40 was identified as a component of the mSin3A/p33(ING1b)/HDAC1 deacetylase complex; the purified p40-associated complex shows strong HDAC activity and Gal-p40 represses transcription; p40 overexpression inhibits cell growth.","method":"Biochemical purification, mass spectrometry, HDAC activity assay, Gal4-luciferase repression assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro enzymatic assay with biochemical purification, single lab","pmids":["15451426"],"is_preprint":false},{"year":2006,"finding":"BRMS1 protein is stabilized by the Hsp90 chaperone; BRMS1 interacts with chaperones DNAJB6 (MRJ), Hsp90, and Hsp70, and also with class II HDACs (HDAC4, 5, 6); BRMS1 turnover is proteasome-dependent.","method":"Yeast two-hybrid, immuno-affinity chromatography, co-immunoprecipitation, proteasome inhibitor treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (Y2H, co-IP, chromatography) in single lab","pmids":["16919237"],"is_preprint":false},{"year":2007,"finding":"BRMS1 inhibits osteopontin (OPN) transcription by abrogating NF-κB activation; a novel NF-κB binding site in the OPN promoter was identified, confirmed by EMSA and ChIP, and HDAC3 participates in OPN suppression via this site.","method":"Luciferase reporter assays, EMSA, chromatin immunoprecipitation (ChIP)","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (reporter assay, EMSA, ChIP) with mechanistic site identification","pmids":["17227585"],"is_preprint":false},{"year":2008,"finding":"BRMS1 suppresses metastasis by increasing cell death during transit through the vasculature (susceptibility to anoikis) and inhibiting colonization at secondary sites; it reduces metastatic outgrowth in multiple organs (lung, bone, liver, brain, etc.).","method":"Intracardiac injection xenograft model, in vitro anoikis assay (poly-HEMA plates), in vivo imaging","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — in vivo multi-organ model plus in vitro mechanistic validation, multiple cell lines","pmids":["18276787"],"is_preprint":false},{"year":2009,"finding":"BRMS1 contains a functional nuclear localization signal (NLS) sufficient for nuclear import, mediated specifically by importin α6; a nuclear export signal (NES) not sensitive to CRM1 inhibitor leptomycin B; and BRMS1 shuttles between nucleus and cytoplasm as shown by interspecies heterokaryon assay.","method":"In vivo NLS/NES assays, yeast two-hybrid (importin α6 interaction), heterokaryon shuttling assay, leptomycin B treatment","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays establishing localization signals and nucleocytoplasmic shuttling","pmids":["19649328"],"is_preprint":false},{"year":2010,"finding":"ING4 is induced by BRMS1 downstream of NF-κB inhibition and suppresses melanoma angiogenesis by inhibiting IL-6 expression; ING4 knockdown abrogates BRMS1-mediated suppression of endothelial cell growth, establishing ING4 as a downstream effector of BRMS1 in angiogenesis regulation.","method":"Genetic epistasis (ING4 knockdown/overexpression in BRMS1-expressing cells), in vitro HUVEC assays, in vivo matrigel plug assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis with rescue experiments, single lab","pmids":["21056991"],"is_preprint":false},{"year":2011,"finding":"TNF-induced phosphorylation of RelA/p65 at S276 promotes direct recruitment of DNMT-1 to the BRMS1 promoter, causing promoter-specific CpG methylation and transcriptional repression of BRMS1; small-molecule inhibition of RelA/p65-DNMT-1 interaction abrogates this repression.","method":"ChIP, methylation-specific PCR, luciferase reporter assay, Co-IP, small-molecule inhibition, site-directed mutagenesis (S276)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including ChIP, Co-IP, mutagenesis, and pharmacological inhibition","pmids":["21765477"],"is_preprint":false},{"year":2011,"finding":"BRMS1 is ubiquitinated and destabilized by the Cul3-SPOP E3 ubiquitin ligase complex; SPOP acts as the adaptor protein for this interaction; SPOP knockdown increases BRMS1 protein levels and represses BRMS1 target genes OPN and uPA.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional ubiquitination assay and gene expression readout, single lab","pmids":["22085717"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of BRMS1 N-terminal region (residues 51–98) reveals an antiparallel coiled-coil motif that homo-oligomerizes into a hexameric conformation (trimer of coiled-coil dimers), as confirmed by hydrodynamic experiments; this N-terminal region mediates molecular clustering relevant to BRMS1 function.","method":"X-ray crystallography, hydrodynamic experiments (solution biophysics)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with biophysical validation in solution","pmids":["21777593"],"is_preprint":false},{"year":2012,"finding":"BRMS1 functions as an E3 ubiquitin ligase toward histone acetyltransferase p300, inducing its polyubiquitination and proteasome-mediated degradation; the evolutionarily conserved CXD motif in BRMS1 is responsible for this E3 ligase activity; mutation of the CXD motif abolishes p300 ubiquitination and dramatically reduces metastasis suppression in vitro and in vivo.","method":"In vitro ubiquitination assay, site-directed mutagenesis (CXD motif), in vivo lung cancer metastasis model, proteasome inhibitor assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 — enzymatic reconstitution of E3 ligase activity with active-site mutagenesis and in vivo functional validation","pmids":["23269275"],"is_preprint":false},{"year":2013,"finding":"The C-terminal NLS2 (amino acids 238–244) of BRMS1 is necessary for metastasis suppression but not strictly for nuclear localization; NLS2-containing constructs co-immunoprecipitate SIN3A in both nucleus and cytoplasm, whereas NLS1-only constructs associate with SIN3A only in the nucleus; NLS2 is required for down-regulation of pro-metastatic miR-10b.","method":"NLS mutagenesis/truncation constructs, xenograft metastasis assay, co-immunoprecipitation, miRNA expression analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — systematic mutagenesis with in vivo functional readout and mechanistic follow-up (SIN3A co-IP, miRNA)","pmids":["23390556"],"is_preprint":false},{"year":2013,"finding":"BRMS1 expression reduces activation of β1 integrin and focal adhesion kinase (FAK), decreases their localization to focal adhesion sites, and impairs cytoskeletal reorganization on collagen/fibronectin, leading to markedly delayed cell adhesion without altering integrin monomer expression levels.","method":"Time-lapse and confocal microscopy, integrin activation assay, 3D culture, focal adhesion imaging","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — multiple imaging modalities with mechanistic readouts, single lab","pmids":["24000122"],"is_preprint":false},{"year":2014,"finding":"Loss of BRMS1 promotes epithelial-to-mesenchymal transition (EMT) in NSCLC cells via NF-κB (RelA/p65)-dependent transcriptional upregulation of Twist1; ChIP shows increased RelA/p65 K310 acetylation at the Twist1 promoter upon BRMS1 knockdown; Twist1 knockdown reverses BRMS1-KD-mediated EMT.","method":"shRNA knockdown, ChIP, EMT marker analysis, genetic epistasis (Twist1 KD in BRMS1-KD background), in vivo lung tumor model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — epistasis with ChIP mechanistic validation and in vivo confirmation, multiple orthogonal methods","pmids":["25368381"],"is_preprint":false},{"year":2015,"finding":"iASPP stabilizes p300 and CBP by interfering with their BRMS1-mediated ubiquitination; iASPP depletion decreases p300/CBP levels in a manner rescued by BRMS1 knockdown, demonstrating that BRMS1 E3 ligase activity toward p300/CBP is counteracted by iASPP.","method":"Co-immunoprecipitation, shRNA knockdown, Western blot, rescue assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with epistasis rescue, single lab","pmids":["25675294"],"is_preprint":false},{"year":2015,"finding":"JARID1C histone demethylase promotes breast cancer metastasis by reducing H3K4me3 at the BRMS1 gene promoter, silencing BRMS1 transcription; JARID1C knockdown increases BRMS1 expression and inhibits cell migration; BRMS1 knockdown reverses the migration inhibition caused by JARID1C silencing.","method":"ChIP (H3K4me3), siRNA knockdown, epistasis rescue assay, migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus epistasis, single lab","pmids":["26182878"],"is_preprint":false},{"year":2016,"finding":"TNF-induced CK2α' phosphorylates nuclear BRMS1 on serine 30 (S30), promoting 14-3-3ε-mediated nuclear export of BRMS1, increased cytoplasmic localization, and subsequent ubiquitin-proteasome degradation; S30 mutation or CK2 inhibitor CX4945 abrogates this and reduces NSCLC metastasis ~60-fold in vivo.","method":"Site-directed mutagenesis (S30), co-immunoprecipitation (14-3-3ε), small-molecule CK2 inhibitor, in vivo orthotopic metastasis model, human NSCLC specimen analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — phosphorylation site mutagenesis, binding partner Co-IP, pharmacological validation, in vivo model, and human tissue confirmation","pmids":["26980766"],"is_preprint":false},{"year":2016,"finding":"BRMS1 is phosphorylated on serine 237 by CDK2; this phosphorylation does not affect nuclear localization, cell cycle progression, or association with mSin3/HDAC complex, but does regulate cell migration; S237 is immediately proximal to the C-terminal NLS.","method":"In vitro CDK2 kinase assay, site-directed mutagenesis (S237), cell cycle analysis, co-immunoprecipitation, migration assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis and functional migration readout","pmids":["26771717"],"is_preprint":false},{"year":2018,"finding":"BRMS1 is an integral component of the LSD1/CoREST corepressor complex; affinity purification/MS identified this interaction; BRMS1 and LSD1 together are required for inhibition of breast cancer cell migration and invasion, and co-regulate target genes including VIM and other metastasis-related genes.","method":"Affinity purification, mass spectrometry, RNA-seq, functional migration/invasion assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — AP-MS identification with functional validation, single lab","pmids":["30416854"],"is_preprint":false},{"year":2018,"finding":"TRIM7 ubiquitinates BRMS1, promoting its degradation and thereby regulating osteosarcoma cell migration, invasion, and chemoresistance; m6A modification of TRIM7 mRNA (mediated by METTL3/YTHDF2) modulates TRIM7 levels and consequently BRMS1 stability.","method":"Co-immunoprecipitation, mass spectrometry, pull-down, ubiquitination assay, RNA immunoprecipitation (m6A), immunofluorescence, PDX mouse model","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, MS, in vitro ubiquitination assay, in vivo PDX model)","pmids":["32853985"],"is_preprint":false},{"year":2018,"finding":"BRMS1 interacts with FANCI via its linker region between two coiled-coil motifs; BRMS1 knockdown/knockout diminishes FANCI and FANCD2 monoubiquitination and FANCD2 foci formation in response to DNA interstrand crosslink (ICL) damage, and causes hypersensitivity to ICLs; BRMS1-FANCI interaction is required for BRMS1's regulatory role in the Fanconi anemia DNA repair pathway.","method":"Co-immunoprecipitation, BRMS1 domain mapping (deletion constructs), FANCD2 immunofluorescence foci, ICL sensitivity assay, CRISPR knockout","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with domain mapping and functional ICL sensitivity readout, single lab","pmids":["30365131"],"is_preprint":false},{"year":2021,"finding":"Phosphorylation status of BRMS1 at S237 regulates its protein interactions with partners involved in cell cycle (e.g., CDKN2A), DNA repair (e.g., BRCA1), and metastasis (e.g., TCF2, POLE2); presence of S237 directly decreases MDA-MB-231 migration in vitro and metastases in vivo.","method":"Quantitative MS interactome (phospho-S237 vs. S237A mutant), in vitro migration assay, in vivo metastasis model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — MS interactome with functional in vivo validation, single lab","pmids":["34788285"],"is_preprint":false},{"year":2022,"finding":"BRMS1v2 A273V SNP abolishes metastasis suppressor function; wild-type BRMS1v2 interacts with nuclear Src to suppress c-fos-mediated transcription; the A273V mutation abrogates this Src interaction, activating c-fos, upregulating CEACAM6, and driving metastasis; c-fos inhibitor T5224 suppresses metastasis in BRMS1v2 A273V/A273V models.","method":"Next-generation sequencing, Co-immunoprecipitation (BRMS1v2-nuclear Src), xenograft and PDO intracardiac injection metastasis models, pharmacological inhibition (T5224)","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — Co-IP mechanistic link, multiple in vivo models, pharmacological rescue, human SNP data","pmids":["36197962"],"is_preprint":false},{"year":2017,"finding":"BRMS1 transcriptionally activates DAPK1 through NF-κB binding sites in the DAPK1 promoter (−200 to −80 bp region); BRMS1 occupancy at this promoter region was confirmed by ChIP; site-directed mutation of NF-κB sites blocks BRMS1-mediated DAPK1 transcriptional activation.","method":"Luciferase reporter assay with deletion/mutation constructs, ChIP, qPCR, Western blot","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 1–2 — promoter dissection with ChIP and site-directed mutagenesis, single lab","pmids":["28339067"],"is_preprint":false},{"year":2013,"finding":"BRMS1 overexpression increases cAMP levels and PKA activity by activating adenylate cyclase via G-protein coupling, and upregulates Cx26 (connexin 26) expression; pertussis toxin pretreatment eliminates BRMS1's effect on cell migration, implicating a G-protein-coupled cAMP signaling pathway in BRMS1-mediated migration suppression.","method":"Radioimmunoassay (cAMP), enzyme immunoassay (AC, PDE, PKA activity), pertussis toxin inhibition, RT-PCR and Western blot (connexins)","journal":"International journal of clinical and experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 — indirect pathway inference via pharmacological inhibition, single lab with limited mechanistic depth","pmids":["24260596"],"is_preprint":false},{"year":2013,"finding":"BRMS1 expression restores P2Y2 purinergic receptor levels and ATP-induced cytosolic calcium mobilization in breast cancer cells, sensitizing them to the antiproliferative effects of extracellular ATP.","method":"Cell proliferation assay, apoptosis assay, calcium imaging, P2Y2 expression analysis","journal":"BioResearch open access","confidence":"Low","confidence_rationale":"Tier 3 — single lab, functional readout without deep mechanistic pathway placement","pmids":["23593560"],"is_preprint":false},{"year":2009,"finding":"Endogenous BRMS1-containing complexes immunoprecipitated from MCF7 cells contain Hsp27, as identified by mass spectrometry.","method":"Immunoprecipitation, mass spectrometry","journal":"Protein expression and purification","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP/MS from one cell line, no functional follow-up","pmids":["19401233"],"is_preprint":false},{"year":2015,"finding":"BRMS1 attenuates TGF-β1-induced EMT and invasion through NF-κB-mediated downregulation of HIF-1α transcript, which in turn reduces Snail and TWIST1 expression; ChIP and luciferase assays confirm HIF-1α as transcriptional regulator of TWIST1 and Snail.","method":"ChIP, luciferase reporter assay, qRT-PCR, Western blot, Matrigel invasion assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (ChIP, reporter, invasion assay) with mechanistic cascade, single lab","pmids":["26520789"],"is_preprint":false}],"current_model":"BRMS1 is a predominantly nuclear metastasis suppressor that functions as a member of mSin3/HDAC chromatin remodeling complexes (interacting with RBP1, mSin3A, and multiple HDACs) to repress transcription of pro-metastatic genes (e.g., OPN, Twist1) via NF-κB inhibition and histone deacetylation; it also acts as an E3 ubiquitin ligase targeting p300/CBP for proteasomal degradation; its activity, localization, and stability are regulated post-translationally by CDK2 phosphorylation (S237), CK2α'-mediated phosphorylation (S30) leading to 14-3-3ε-dependent nuclear export and proteasomal degradation, and ubiquitination by Cul3-SPOP and TRIM7 complexes; through these mechanisms BRMS1 suppresses multiple steps of the metastatic cascade including anoikis resistance, integrin/FAK-mediated adhesion, cell motility, angiogenesis, and EMT, without affecting primary tumor growth."},"narrative":{"teleology":[{"year":2000,"claim":"The foundational question of whether a gene at 11q13 could suppress metastasis without affecting primary tumor growth was answered, establishing BRMS1 as a bona fide metastasis suppressor.","evidence":"Stable transfection into MDA-MB-435 and MDA-MB-231 cells with in vivo xenograft lung and lymph node metastasis assays","pmids":["10850410"],"confidence":"High","gaps":["Mechanism of metastasis suppression unknown","No molecular targets or interacting partners identified","Activity in non-breast cancer contexts untested"]},{"year":2000,"claim":"An early phenotypic clue emerged: BRMS1 restored gap junctional intercellular communication and modestly inhibited motility, suggesting its effects operate through cell communication rather than protease activity or ECM adhesion.","evidence":"In vitro GJIC, motility, adhesion, and MMP expression assays in breast carcinoma lines","pmids":["11827072"],"confidence":"Medium","gaps":["Molecular mechanism linking BRMS1 to GJIC unknown","No transcriptional targets identified"]},{"year":2003,"claim":"The mechanism shifted from phenotype to molecular complex: BRMS1 was shown to be a component of mSin3/HDAC corepressor complexes, explaining its metastasis suppression through transcriptional repression via histone deacetylation.","evidence":"Yeast two-hybrid (RBP1), reciprocal co-immunoprecipitation with HDAC1/mSin3A, enzymatic HDAC activity, and Gal4-reporter transcriptional repression assay","pmids":["14581478"],"confidence":"High","gaps":["Specific gene targets of BRMS1-mediated repression unidentified","Relative contribution of different HDACs unclear","Whether BRMS1 has functions independent of mSin3 complexes unknown"]},{"year":2007,"claim":"The first direct transcriptional target was identified: BRMS1 represses OPN via a novel NF-κB binding site, with HDAC3 participating in this repression, establishing NF-κB inhibition as a central mechanism.","evidence":"Luciferase reporter assays, EMSA, and ChIP on OPN promoter NF-κB site","pmids":["17227585"],"confidence":"High","gaps":["Breadth of NF-κB-dependent target genes unknown","Mechanism by which BRMS1 inhibits NF-κB activation not defined"]},{"year":2008,"claim":"The stage of the metastatic cascade where BRMS1 acts was pinpointed: it increases anoikis sensitivity during vascular transit and inhibits colonization at secondary sites across multiple organs.","evidence":"Intracardiac injection xenograft model with multi-organ analysis plus in vitro anoikis assays","pmids":["18276787"],"confidence":"High","gaps":["Molecular pathway linking BRMS1 to anoikis sensitization not elucidated","Whether effects are organ-specific or universal unclear"]},{"year":2009,"claim":"BRMS1 was shown to shuttle between nucleus and cytoplasm via a functional NLS (recognized by importin α6) and a CRM1-independent NES, establishing that its localization is dynamically regulated.","evidence":"NLS/NES mapping constructs, yeast two-hybrid with importin α6, heterokaryon shuttling assay, leptomycin B insensitivity","pmids":["19649328"],"confidence":"High","gaps":["Signals or stimuli regulating shuttling unknown","CRM1-independent export pathway uncharacterized","Functional significance of cytoplasmic pool unclear"]},{"year":2011,"claim":"Three key advances converged: the crystal structure revealed a hexameric N-terminal coiled-coil architecture; Cul3-SPOP was identified as an E3 ligase degrading BRMS1; and TNF/RelA-p65-driven DNMT1 recruitment to the BRMS1 promoter was shown to silence BRMS1 itself via CpG methylation.","evidence":"X-ray crystallography with biophysical validation (hexamer); Co-IP and ubiquitination assays (Cul3-SPOP); ChIP, methylation-specific PCR, mutagenesis, and pharmacological inhibition (DNMT1 pathway)","pmids":["21777593","22085717","21765477"],"confidence":"High","gaps":["Functional role of hexamerization in complex assembly unknown","Additional E3 ligases targeting BRMS1 not yet surveyed","Whether DNMT1-mediated silencing operates in all tumor types unclear"]},{"year":2012,"claim":"BRMS1 was discovered to have intrinsic E3 ubiquitin ligase activity, targeting p300 for proteasomal degradation through a conserved CXD motif; this activity is essential for metastasis suppression, revealing a non-transcriptional effector mechanism.","evidence":"In vitro ubiquitination reconstitution, CXD motif mutagenesis, in vivo lung cancer metastasis model","pmids":["23269275"],"confidence":"High","gaps":["Whether substrates beyond p300/CBP exist is unknown","Structural basis of CXD-mediated E3 activity unresolved","Relationship between E3 ligase function and mSin3 complex membership unclear"]},{"year":2013,"claim":"Functional dissection of BRMS1 localization signals revealed that the C-terminal NLS2 is dispensable for nuclear import but essential for metastasis suppression and SIN3A interaction in both compartments, and that BRMS1 suppresses integrin β1/FAK activation at focal adhesions to delay cell adhesion.","evidence":"NLS mutagenesis/truncation with xenograft metastasis assay and SIN3A co-IP (NLS2); confocal microscopy, integrin activation assays, 3D culture (integrin/FAK)","pmids":["23390556","24000122"],"confidence":"High","gaps":["Mechanism linking BRMS1 to integrin activation status unknown","Whether cytoplasmic SIN3A complex has distinct gene targets is unresolved"]},{"year":2014,"claim":"BRMS1 was shown to suppress EMT by preventing NF-κB-dependent Twist1 transcription; loss of BRMS1 increased RelA/p65 K310 acetylation at the Twist1 promoter, connecting BRMS1's chromatin-remodeling role to the EMT program.","evidence":"shRNA knockdown, ChIP at Twist1 promoter, epistasis with Twist1 KD, in vivo lung tumor model","pmids":["25368381"],"confidence":"High","gaps":["Whether BRMS1 directly deacetylates RelA K310 or acts indirectly unclear","Contribution of EMT suppression relative to anoikis sensitization in vivo unquantified"]},{"year":2016,"claim":"Two phosphorylation events regulating BRMS1 were mapped: CK2α′ phosphorylates S30 to trigger 14-3-3ε-mediated nuclear export and degradation (targetable by CX4945), while CDK2 phosphorylates S237 to regulate migration-related protein interactions without affecting mSin3 complex association.","evidence":"Site-directed mutagenesis (S30, S237), co-IP with 14-3-3ε, CK2 inhibitor CX4945, in vitro CDK2 kinase assay, in vivo orthotopic metastasis model","pmids":["26980766","26771717"],"confidence":"High","gaps":["Full phosphoproteome of BRMS1 not mapped","Whether S30 and S237 phosphorylation events are coordinated or independent unknown","Therapeutic window of CK2 inhibition for BRMS1 stabilization not established"]},{"year":2018,"claim":"BRMS1's functional repertoire expanded beyond mSin3: it was identified as a component of the LSD1/CoREST corepressor complex co-regulating metastasis genes, and separately shown to promote FANCI/FANCD2 monoubiquitination for DNA interstrand crosslink repair; additionally, TRIM7 was identified as a second E3 ligase degrading BRMS1.","evidence":"AP-MS and RNA-seq with migration/invasion assays (LSD1/CoREST); Co-IP, domain mapping, ICL sensitivity in CRISPR-KO cells (FANCI); Co-IP, ubiquitination assay, PDX model (TRIM7)","pmids":["30416854","30365131","32853985"],"confidence":"Medium","gaps":["Whether LSD1/CoREST and mSin3 complexes have overlapping or distinct BRMS1-dependent target genes unknown","Structural basis of BRMS1-FANCI interaction not resolved","Relative contributions of SPOP vs TRIM7 to BRMS1 turnover in different tissues unclear"]},{"year":2022,"claim":"A naturally occurring SNP (BRMS1v2 A273V) was shown to abolish metastasis suppression by disrupting interaction with nuclear Src, derepressing c-fos/CEACAM6 transcription, which was therapeutically targetable with c-fos inhibitor T5224.","evidence":"NGS variant identification, co-IP (BRMS1v2–nuclear Src), xenograft and PDO intracardiac injection models, pharmacological rescue with T5224","pmids":["36197962"],"confidence":"High","gaps":["Population frequency and penetrance of A273V not determined from this study","Whether nuclear Src interaction is relevant to BRMS1v1 function unknown","Structural basis of Src-BRMS1v2 interaction unresolved"]},{"year":null,"claim":"Key open questions include how BRMS1 partitions between mSin3/HDAC, LSD1/CoREST, and other complexes; the full spectrum of E3 ligase substrates beyond p300/CBP; the structural basis for its dual corepressor-component and E3-ligase activities; and whether BRMS1-stabilizing strategies (CK2 or TRIM7 inhibition) can be translated therapeutically.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrative structural model of full-length BRMS1 in complex","No genome-wide identification of direct BRMS1-bound chromatin sites (e.g., genome-wide ChIP-seq)","Therapeutic applicability of BRMS1 stabilization not tested in clinical settings"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[12,16]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,5,15,25]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,13,18,19]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,13,18]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,5,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,15,25]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,12,21]}],"complexes":["mSin3A/HDAC corepressor complex","LSD1/CoREST corepressor complex"],"partners":["SIN3A","HDAC1","RBP1","SPOP","TRIM7","FANCI","KPNA5","EP300"],"other_free_text":[]},"mechanistic_narrative":"BRMS1 is a metastasis suppressor that inhibits tumor dissemination without affecting primary tumor growth by acting through chromatin remodeling complexes and direct ubiquitin ligase activity. BRMS1 integrates into mSin3/HDAC and LSD1/CoREST corepressor complexes to repress transcription of pro-metastatic genes such as OPN, Twist1, and HIF-1α, primarily by antagonizing NF-κB-dependent transcription and modulating histone acetylation [PMID:14581478, PMID:17227585, PMID:25368381, PMID:30416854]. BRMS1 also functions as an E3 ubiquitin ligase that targets the histone acetyltransferases p300/CBP for proteasomal degradation through a conserved CXD motif essential for its metastasis-suppressive activity, and a splice variant (BRMS1v2) interacts with nuclear Src to repress c-fos-mediated transcription [PMID:23269275, PMID:36197962]. BRMS1 protein stability and nuclear-cytoplasmic shuttling are regulated by CK2α′-mediated S30 phosphorylation triggering 14-3-3ε-dependent nuclear export and degradation, CDK2-mediated S237 phosphorylation controlling migration-relevant protein interactions, and ubiquitination by Cul3-SPOP and TRIM7 E3 ligase complexes [PMID:26980766, PMID:26771717, PMID:22085717, PMID:32853985]."},"prefetch_data":{"uniprot":{"accession":"Q9HCU9","full_name":"Breast cancer metastasis-suppressor 1","aliases":[],"length_aa":246,"mass_kda":28.5,"function":"Transcriptional repressor. Down-regulates transcription activation by NF-kappa-B by promoting the deacetylation of RELA at 'Lys-310'. Promotes HDAC1 binding to promoter regions. Down-regulates expression of anti-apoptotic genes that are controlled by NF-kappa-B. Promotes apoptosis in cells that have inadequate adherence to a substrate, a process called anoikis, and may thereby inhibit metastasis. May be a mediator of metastasis suppression in breast carcinoma","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9HCU9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BRMS1","classification":"Not Classified","n_dependent_lines":309,"n_total_lines":1208,"dependency_fraction":0.25579470198675497},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BRMS1","total_profiled":1310},"omim":[{"mim_id":"618514","title":"BRMS1-LIKE TRANSCRIPTIONAL REPRESSOR; BRMS1L","url":"https://www.omim.org/entry/618514"},{"mim_id":"606259","title":"BRMS1 TRANSCRIPTIONAL REPRESSOR AND ANOIKIS REGULATOR; BRMS1","url":"https://www.omim.org/entry/606259"},{"mim_id":"604215","title":"INHIBITOR OF GROWTH 2; 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reports","url":"https://pubmed.ncbi.nlm.nih.gov/30365131","citation_count":3,"is_preprint":false},{"pmid":"28339067","id":"PMC_28339067","title":"Characterization of DAPK1 as a novel transcriptional target of BRMS1.","date":"2017","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28339067","citation_count":3,"is_preprint":false},{"pmid":"34788285","id":"PMC_34788285","title":"Perturbation of BRMS1 interactome reveals pathways that impact metastasis.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34788285","citation_count":3,"is_preprint":false},{"pmid":"32405371","id":"PMC_32405371","title":"Metastasis inhibition by BRMS1 and miR-31 replacement therapy in claudin-low cell lines.","date":"2020","source":"Iranian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32405371","citation_count":3,"is_preprint":false},{"pmid":"39396919","id":"PMC_39396919","title":"Anti-metastatic Effects of Bee Venom and Melittin in Breast Cancer Cells by Upregulation of BRMS1 and DRG1 Genes.","date":"2024","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/39396919","citation_count":3,"is_preprint":false},{"pmid":"19621595","id":"PMC_19621595","title":"[Expression of gene BRMS1 and CD44v6 protein in supraglottic laryngeal carcinoma and its clinical significance].","date":"2009","source":"Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/19621595","citation_count":3,"is_preprint":false},{"pmid":"34096224","id":"PMC_34096224","title":"Metastasis Inhibition by Cell Type Specific Expression of BRMS1 Gene under The Regulation of miR200 Family Response Elements.","date":"2021","source":"Cell journal","url":"https://pubmed.ncbi.nlm.nih.gov/34096224","citation_count":3,"is_preprint":false},{"pmid":"32742405","id":"PMC_32742405","title":"Anti-tumor peptide SA12 inhibits metastasis of MDA-MB-231 and MCF-7 breast cancer cells via increasing expression of the tumor metastasis suppressor genes, CDH1, nm23-H1 and BRMS1.","date":"2020","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32742405","citation_count":3,"is_preprint":false},{"pmid":"22239051","id":"PMC_22239051","title":"[Expression of BRMS1 gene protein in nasal and paranasal sinus carcinomas].","date":"2011","source":"Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/22239051","citation_count":3,"is_preprint":false},{"pmid":"37296870","id":"PMC_37296870","title":"BRMS1 in Gliomas-An Expression Analysis.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37296870","citation_count":2,"is_preprint":false},{"pmid":"40106959","id":"PMC_40106959","title":"Estradiol conjugation to estrogen receptorα upregulates Brms1 expression mediating M2 polarization of alveolar macrophages and exacerbating airway inflammation in asthmatic mice.","date":"2025","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40106959","citation_count":1,"is_preprint":false},{"pmid":"16963426","id":"PMC_16963426","title":"[Progress on breast cancer metastasis suppressor 1 (BRMS1)].","date":"2006","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/16963426","citation_count":1,"is_preprint":false},{"pmid":"40665664","id":"PMC_40665664","title":"BRMS1 suppresses the PI3K/AKT/mTOR pathway to regulate autophagy in multiple myeloma.","date":"2025","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/40665664","citation_count":0,"is_preprint":false},{"pmid":"25187687","id":"PMC_25187687","title":"Modelling and simulation of mutant alleles of breast cancer metastasis suppressor 1 (BRMS1) gene.","date":"2014","source":"Bioinformation","url":"https://pubmed.ncbi.nlm.nih.gov/25187687","citation_count":0,"is_preprint":false},{"pmid":"31394646","id":"PMC_31394646","title":"Down-regulation of BRMS1 mRNA Expression in Breast Cancer is not Related to the Presence of Axillary Node Metastasis.","date":"2005","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/31394646","citation_count":0,"is_preprint":false},{"pmid":"39660332","id":"PMC_39660332","title":"Erratum: Down-regulation of BRMS1 by DNA hypermethylation and its association with metastatic progression in triple-negative breast cancer.","date":"2024","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39660332","citation_count":0,"is_preprint":false},{"pmid":"23167184","id":"PMC_23167184","title":"[The study of expression of BRMS1 gene protein and the expression of BRMS1 gene promotor area methylation in supraglottic laryngeal carcinoma and its clinical significance].","date":"2012","source":"Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/23167184","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45765,"output_tokens":6911,"usd":0.12048},"stage2":{"model":"claude-opus-4-6","input_tokens":10665,"output_tokens":3780,"usd":0.221738},"total_usd":0.342218,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"BRMS1 was identified as a metastasis suppressor gene encoded at chromosome 11q13.1-q13.2; stable transfection into MDA-MB-435 and MDA-MB-231 breast carcinoma cells suppressed metastasis to lungs and regional lymph nodes without inhibiting primary tumor formation.\",\n      \"method\": \"Differential display, stable transfection, in vivo xenograft metastasis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated in two cell lines with in vivo functional readout; foundational paper with 233 citations\",\n      \"pmids\": [\"10850410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"BRMS1 expression restored homotypic gap junctional intercellular communication (GJIC) in human breast carcinoma cells and modestly inhibited cell motility, without affecting adhesion to ECM components, MMP expression, or other known metastasis suppressors.\",\n      \"method\": \"In vitro functional assays (GJIC, motility, adhesion, soft agar, MMP expression)\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro assays in two cell lines, single lab\",\n      \"pmids\": [\"11827072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"BRMS1 interacts with retinoblastoma-binding protein 1 (RBP1) and at least seven members of the mSin3 histone deacetylase (HDAC) complex, co-immunoprecipitates enzymatically active HDAC proteins, and represses transcription when recruited to a Gal4 promoter; BRMS1 exists in large ~1.4–1.9 MDa mSin3 complexes and also smaller complexes with HDAC1; C-terminal 42 amino acids are not critical for mSin3 interaction.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vivo transcription repression assay, deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — yeast two-hybrid confirmed by reciprocal Co-IP, enzymatic activity measured, functional transcriptional repression assay with deletion mapping; 141 citations\",\n      \"pmids\": [\"14581478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A BRMS1-homologous protein p40 was identified as a component of the mSin3A/p33(ING1b)/HDAC1 deacetylase complex; the purified p40-associated complex shows strong HDAC activity and Gal-p40 represses transcription; p40 overexpression inhibits cell growth.\",\n      \"method\": \"Biochemical purification, mass spectrometry, HDAC activity assay, Gal4-luciferase repression assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with biochemical purification, single lab\",\n      \"pmids\": [\"15451426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BRMS1 protein is stabilized by the Hsp90 chaperone; BRMS1 interacts with chaperones DNAJB6 (MRJ), Hsp90, and Hsp70, and also with class II HDACs (HDAC4, 5, 6); BRMS1 turnover is proteasome-dependent.\",\n      \"method\": \"Yeast two-hybrid, immuno-affinity chromatography, co-immunoprecipitation, proteasome inhibitor treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (Y2H, co-IP, chromatography) in single lab\",\n      \"pmids\": [\"16919237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BRMS1 inhibits osteopontin (OPN) transcription by abrogating NF-κB activation; a novel NF-κB binding site in the OPN promoter was identified, confirmed by EMSA and ChIP, and HDAC3 participates in OPN suppression via this site.\",\n      \"method\": \"Luciferase reporter assays, EMSA, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (reporter assay, EMSA, ChIP) with mechanistic site identification\",\n      \"pmids\": [\"17227585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BRMS1 suppresses metastasis by increasing cell death during transit through the vasculature (susceptibility to anoikis) and inhibiting colonization at secondary sites; it reduces metastatic outgrowth in multiple organs (lung, bone, liver, brain, etc.).\",\n      \"method\": \"Intracardiac injection xenograft model, in vitro anoikis assay (poly-HEMA plates), in vivo imaging\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo multi-organ model plus in vitro mechanistic validation, multiple cell lines\",\n      \"pmids\": [\"18276787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BRMS1 contains a functional nuclear localization signal (NLS) sufficient for nuclear import, mediated specifically by importin α6; a nuclear export signal (NES) not sensitive to CRM1 inhibitor leptomycin B; and BRMS1 shuttles between nucleus and cytoplasm as shown by interspecies heterokaryon assay.\",\n      \"method\": \"In vivo NLS/NES assays, yeast two-hybrid (importin α6 interaction), heterokaryon shuttling assay, leptomycin B treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays establishing localization signals and nucleocytoplasmic shuttling\",\n      \"pmids\": [\"19649328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ING4 is induced by BRMS1 downstream of NF-κB inhibition and suppresses melanoma angiogenesis by inhibiting IL-6 expression; ING4 knockdown abrogates BRMS1-mediated suppression of endothelial cell growth, establishing ING4 as a downstream effector of BRMS1 in angiogenesis regulation.\",\n      \"method\": \"Genetic epistasis (ING4 knockdown/overexpression in BRMS1-expressing cells), in vitro HUVEC assays, in vivo matrigel plug assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with rescue experiments, single lab\",\n      \"pmids\": [\"21056991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TNF-induced phosphorylation of RelA/p65 at S276 promotes direct recruitment of DNMT-1 to the BRMS1 promoter, causing promoter-specific CpG methylation and transcriptional repression of BRMS1; small-molecule inhibition of RelA/p65-DNMT-1 interaction abrogates this repression.\",\n      \"method\": \"ChIP, methylation-specific PCR, luciferase reporter assay, Co-IP, small-molecule inhibition, site-directed mutagenesis (S276)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including ChIP, Co-IP, mutagenesis, and pharmacological inhibition\",\n      \"pmids\": [\"21765477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRMS1 is ubiquitinated and destabilized by the Cul3-SPOP E3 ubiquitin ligase complex; SPOP acts as the adaptor protein for this interaction; SPOP knockdown increases BRMS1 protein levels and represses BRMS1 target genes OPN and uPA.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional ubiquitination assay and gene expression readout, single lab\",\n      \"pmids\": [\"22085717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of BRMS1 N-terminal region (residues 51–98) reveals an antiparallel coiled-coil motif that homo-oligomerizes into a hexameric conformation (trimer of coiled-coil dimers), as confirmed by hydrodynamic experiments; this N-terminal region mediates molecular clustering relevant to BRMS1 function.\",\n      \"method\": \"X-ray crystallography, hydrodynamic experiments (solution biophysics)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with biophysical validation in solution\",\n      \"pmids\": [\"21777593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BRMS1 functions as an E3 ubiquitin ligase toward histone acetyltransferase p300, inducing its polyubiquitination and proteasome-mediated degradation; the evolutionarily conserved CXD motif in BRMS1 is responsible for this E3 ligase activity; mutation of the CXD motif abolishes p300 ubiquitination and dramatically reduces metastasis suppression in vitro and in vivo.\",\n      \"method\": \"In vitro ubiquitination assay, site-directed mutagenesis (CXD motif), in vivo lung cancer metastasis model, proteasome inhibitor assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — enzymatic reconstitution of E3 ligase activity with active-site mutagenesis and in vivo functional validation\",\n      \"pmids\": [\"23269275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The C-terminal NLS2 (amino acids 238–244) of BRMS1 is necessary for metastasis suppression but not strictly for nuclear localization; NLS2-containing constructs co-immunoprecipitate SIN3A in both nucleus and cytoplasm, whereas NLS1-only constructs associate with SIN3A only in the nucleus; NLS2 is required for down-regulation of pro-metastatic miR-10b.\",\n      \"method\": \"NLS mutagenesis/truncation constructs, xenograft metastasis assay, co-immunoprecipitation, miRNA expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutagenesis with in vivo functional readout and mechanistic follow-up (SIN3A co-IP, miRNA)\",\n      \"pmids\": [\"23390556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BRMS1 expression reduces activation of β1 integrin and focal adhesion kinase (FAK), decreases their localization to focal adhesion sites, and impairs cytoskeletal reorganization on collagen/fibronectin, leading to markedly delayed cell adhesion without altering integrin monomer expression levels.\",\n      \"method\": \"Time-lapse and confocal microscopy, integrin activation assay, 3D culture, focal adhesion imaging\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple imaging modalities with mechanistic readouts, single lab\",\n      \"pmids\": [\"24000122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of BRMS1 promotes epithelial-to-mesenchymal transition (EMT) in NSCLC cells via NF-κB (RelA/p65)-dependent transcriptional upregulation of Twist1; ChIP shows increased RelA/p65 K310 acetylation at the Twist1 promoter upon BRMS1 knockdown; Twist1 knockdown reverses BRMS1-KD-mediated EMT.\",\n      \"method\": \"shRNA knockdown, ChIP, EMT marker analysis, genetic epistasis (Twist1 KD in BRMS1-KD background), in vivo lung tumor model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with ChIP mechanistic validation and in vivo confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"25368381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"iASPP stabilizes p300 and CBP by interfering with their BRMS1-mediated ubiquitination; iASPP depletion decreases p300/CBP levels in a manner rescued by BRMS1 knockdown, demonstrating that BRMS1 E3 ligase activity toward p300/CBP is counteracted by iASPP.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, Western blot, rescue assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with epistasis rescue, single lab\",\n      \"pmids\": [\"25675294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JARID1C histone demethylase promotes breast cancer metastasis by reducing H3K4me3 at the BRMS1 gene promoter, silencing BRMS1 transcription; JARID1C knockdown increases BRMS1 expression and inhibits cell migration; BRMS1 knockdown reverses the migration inhibition caused by JARID1C silencing.\",\n      \"method\": \"ChIP (H3K4me3), siRNA knockdown, epistasis rescue assay, migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus epistasis, single lab\",\n      \"pmids\": [\"26182878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TNF-induced CK2α' phosphorylates nuclear BRMS1 on serine 30 (S30), promoting 14-3-3ε-mediated nuclear export of BRMS1, increased cytoplasmic localization, and subsequent ubiquitin-proteasome degradation; S30 mutation or CK2 inhibitor CX4945 abrogates this and reduces NSCLC metastasis ~60-fold in vivo.\",\n      \"method\": \"Site-directed mutagenesis (S30), co-immunoprecipitation (14-3-3ε), small-molecule CK2 inhibitor, in vivo orthotopic metastasis model, human NSCLC specimen analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — phosphorylation site mutagenesis, binding partner Co-IP, pharmacological validation, in vivo model, and human tissue confirmation\",\n      \"pmids\": [\"26980766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BRMS1 is phosphorylated on serine 237 by CDK2; this phosphorylation does not affect nuclear localization, cell cycle progression, or association with mSin3/HDAC complex, but does regulate cell migration; S237 is immediately proximal to the C-terminal NLS.\",\n      \"method\": \"In vitro CDK2 kinase assay, site-directed mutagenesis (S237), cell cycle analysis, co-immunoprecipitation, migration assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis and functional migration readout\",\n      \"pmids\": [\"26771717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BRMS1 is an integral component of the LSD1/CoREST corepressor complex; affinity purification/MS identified this interaction; BRMS1 and LSD1 together are required for inhibition of breast cancer cell migration and invasion, and co-regulate target genes including VIM and other metastasis-related genes.\",\n      \"method\": \"Affinity purification, mass spectrometry, RNA-seq, functional migration/invasion assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — AP-MS identification with functional validation, single lab\",\n      \"pmids\": [\"30416854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM7 ubiquitinates BRMS1, promoting its degradation and thereby regulating osteosarcoma cell migration, invasion, and chemoresistance; m6A modification of TRIM7 mRNA (mediated by METTL3/YTHDF2) modulates TRIM7 levels and consequently BRMS1 stability.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, pull-down, ubiquitination assay, RNA immunoprecipitation (m6A), immunofluorescence, PDX mouse model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, MS, in vitro ubiquitination assay, in vivo PDX model)\",\n      \"pmids\": [\"32853985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BRMS1 interacts with FANCI via its linker region between two coiled-coil motifs; BRMS1 knockdown/knockout diminishes FANCI and FANCD2 monoubiquitination and FANCD2 foci formation in response to DNA interstrand crosslink (ICL) damage, and causes hypersensitivity to ICLs; BRMS1-FANCI interaction is required for BRMS1's regulatory role in the Fanconi anemia DNA repair pathway.\",\n      \"method\": \"Co-immunoprecipitation, BRMS1 domain mapping (deletion constructs), FANCD2 immunofluorescence foci, ICL sensitivity assay, CRISPR knockout\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping and functional ICL sensitivity readout, single lab\",\n      \"pmids\": [\"30365131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Phosphorylation status of BRMS1 at S237 regulates its protein interactions with partners involved in cell cycle (e.g., CDKN2A), DNA repair (e.g., BRCA1), and metastasis (e.g., TCF2, POLE2); presence of S237 directly decreases MDA-MB-231 migration in vitro and metastases in vivo.\",\n      \"method\": \"Quantitative MS interactome (phospho-S237 vs. S237A mutant), in vitro migration assay, in vivo metastasis model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS interactome with functional in vivo validation, single lab\",\n      \"pmids\": [\"34788285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BRMS1v2 A273V SNP abolishes metastasis suppressor function; wild-type BRMS1v2 interacts with nuclear Src to suppress c-fos-mediated transcription; the A273V mutation abrogates this Src interaction, activating c-fos, upregulating CEACAM6, and driving metastasis; c-fos inhibitor T5224 suppresses metastasis in BRMS1v2 A273V/A273V models.\",\n      \"method\": \"Next-generation sequencing, Co-immunoprecipitation (BRMS1v2-nuclear Src), xenograft and PDO intracardiac injection metastasis models, pharmacological inhibition (T5224)\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP mechanistic link, multiple in vivo models, pharmacological rescue, human SNP data\",\n      \"pmids\": [\"36197962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRMS1 transcriptionally activates DAPK1 through NF-κB binding sites in the DAPK1 promoter (−200 to −80 bp region); BRMS1 occupancy at this promoter region was confirmed by ChIP; site-directed mutation of NF-κB sites blocks BRMS1-mediated DAPK1 transcriptional activation.\",\n      \"method\": \"Luciferase reporter assay with deletion/mutation constructs, ChIP, qPCR, Western blot\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — promoter dissection with ChIP and site-directed mutagenesis, single lab\",\n      \"pmids\": [\"28339067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BRMS1 overexpression increases cAMP levels and PKA activity by activating adenylate cyclase via G-protein coupling, and upregulates Cx26 (connexin 26) expression; pertussis toxin pretreatment eliminates BRMS1's effect on cell migration, implicating a G-protein-coupled cAMP signaling pathway in BRMS1-mediated migration suppression.\",\n      \"method\": \"Radioimmunoassay (cAMP), enzyme immunoassay (AC, PDE, PKA activity), pertussis toxin inhibition, RT-PCR and Western blot (connexins)\",\n      \"journal\": \"International journal of clinical and experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — indirect pathway inference via pharmacological inhibition, single lab with limited mechanistic depth\",\n      \"pmids\": [\"24260596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BRMS1 expression restores P2Y2 purinergic receptor levels and ATP-induced cytosolic calcium mobilization in breast cancer cells, sensitizing them to the antiproliferative effects of extracellular ATP.\",\n      \"method\": \"Cell proliferation assay, apoptosis assay, calcium imaging, P2Y2 expression analysis\",\n      \"journal\": \"BioResearch open access\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional readout without deep mechanistic pathway placement\",\n      \"pmids\": [\"23593560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Endogenous BRMS1-containing complexes immunoprecipitated from MCF7 cells contain Hsp27, as identified by mass spectrometry.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/MS from one cell line, no functional follow-up\",\n      \"pmids\": [\"19401233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BRMS1 attenuates TGF-β1-induced EMT and invasion through NF-κB-mediated downregulation of HIF-1α transcript, which in turn reduces Snail and TWIST1 expression; ChIP and luciferase assays confirm HIF-1α as transcriptional regulator of TWIST1 and Snail.\",\n      \"method\": \"ChIP, luciferase reporter assay, qRT-PCR, Western blot, Matrigel invasion assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (ChIP, reporter, invasion assay) with mechanistic cascade, single lab\",\n      \"pmids\": [\"26520789\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BRMS1 is a predominantly nuclear metastasis suppressor that functions as a member of mSin3/HDAC chromatin remodeling complexes (interacting with RBP1, mSin3A, and multiple HDACs) to repress transcription of pro-metastatic genes (e.g., OPN, Twist1) via NF-κB inhibition and histone deacetylation; it also acts as an E3 ubiquitin ligase targeting p300/CBP for proteasomal degradation; its activity, localization, and stability are regulated post-translationally by CDK2 phosphorylation (S237), CK2α'-mediated phosphorylation (S30) leading to 14-3-3ε-dependent nuclear export and proteasomal degradation, and ubiquitination by Cul3-SPOP and TRIM7 complexes; through these mechanisms BRMS1 suppresses multiple steps of the metastatic cascade including anoikis resistance, integrin/FAK-mediated adhesion, cell motility, angiogenesis, and EMT, without affecting primary tumor growth.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"BRMS1 is a metastasis suppressor that inhibits tumor dissemination without affecting primary tumor growth by acting through chromatin remodeling complexes and direct ubiquitin ligase activity. BRMS1 integrates into mSin3/HDAC and LSD1/CoREST corepressor complexes to repress transcription of pro-metastatic genes such as OPN, Twist1, and HIF-1α, primarily by antagonizing NF-κB-dependent transcription and modulating histone acetylation [PMID:14581478, PMID:17227585, PMID:25368381, PMID:30416854]. BRMS1 also functions as an E3 ubiquitin ligase that targets the histone acetyltransferases p300/CBP for proteasomal degradation through a conserved CXD motif essential for its metastasis-suppressive activity, and a splice variant (BRMS1v2) interacts with nuclear Src to repress c-fos-mediated transcription [PMID:23269275, PMID:36197962]. BRMS1 protein stability and nuclear-cytoplasmic shuttling are regulated by CK2α′-mediated S30 phosphorylation triggering 14-3-3ε-dependent nuclear export and degradation, CDK2-mediated S237 phosphorylation controlling migration-relevant protein interactions, and ubiquitination by Cul3-SPOP and TRIM7 E3 ligase complexes [PMID:26980766, PMID:26771717, PMID:22085717, PMID:32853985].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The foundational question of whether a gene at 11q13 could suppress metastasis without affecting primary tumor growth was answered, establishing BRMS1 as a bona fide metastasis suppressor.\",\n      \"evidence\": \"Stable transfection into MDA-MB-435 and MDA-MB-231 cells with in vivo xenograft lung and lymph node metastasis assays\",\n      \"pmids\": [\"10850410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of metastasis suppression unknown\", \"No molecular targets or interacting partners identified\", \"Activity in non-breast cancer contexts untested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"An early phenotypic clue emerged: BRMS1 restored gap junctional intercellular communication and modestly inhibited motility, suggesting its effects operate through cell communication rather than protease activity or ECM adhesion.\",\n      \"evidence\": \"In vitro GJIC, motility, adhesion, and MMP expression assays in breast carcinoma lines\",\n      \"pmids\": [\"11827072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking BRMS1 to GJIC unknown\", \"No transcriptional targets identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The mechanism shifted from phenotype to molecular complex: BRMS1 was shown to be a component of mSin3/HDAC corepressor complexes, explaining its metastasis suppression through transcriptional repression via histone deacetylation.\",\n      \"evidence\": \"Yeast two-hybrid (RBP1), reciprocal co-immunoprecipitation with HDAC1/mSin3A, enzymatic HDAC activity, and Gal4-reporter transcriptional repression assay\",\n      \"pmids\": [\"14581478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific gene targets of BRMS1-mediated repression unidentified\", \"Relative contribution of different HDACs unclear\", \"Whether BRMS1 has functions independent of mSin3 complexes unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The first direct transcriptional target was identified: BRMS1 represses OPN via a novel NF-κB binding site, with HDAC3 participating in this repression, establishing NF-κB inhibition as a central mechanism.\",\n      \"evidence\": \"Luciferase reporter assays, EMSA, and ChIP on OPN promoter NF-κB site\",\n      \"pmids\": [\"17227585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Breadth of NF-κB-dependent target genes unknown\", \"Mechanism by which BRMS1 inhibits NF-κB activation not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The stage of the metastatic cascade where BRMS1 acts was pinpointed: it increases anoikis sensitivity during vascular transit and inhibits colonization at secondary sites across multiple organs.\",\n      \"evidence\": \"Intracardiac injection xenograft model with multi-organ analysis plus in vitro anoikis assays\",\n      \"pmids\": [\"18276787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway linking BRMS1 to anoikis sensitization not elucidated\", \"Whether effects are organ-specific or universal unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"BRMS1 was shown to shuttle between nucleus and cytoplasm via a functional NLS (recognized by importin α6) and a CRM1-independent NES, establishing that its localization is dynamically regulated.\",\n      \"evidence\": \"NLS/NES mapping constructs, yeast two-hybrid with importin α6, heterokaryon shuttling assay, leptomycin B insensitivity\",\n      \"pmids\": [\"19649328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals or stimuli regulating shuttling unknown\", \"CRM1-independent export pathway uncharacterized\", \"Functional significance of cytoplasmic pool unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Three key advances converged: the crystal structure revealed a hexameric N-terminal coiled-coil architecture; Cul3-SPOP was identified as an E3 ligase degrading BRMS1; and TNF/RelA-p65-driven DNMT1 recruitment to the BRMS1 promoter was shown to silence BRMS1 itself via CpG methylation.\",\n      \"evidence\": \"X-ray crystallography with biophysical validation (hexamer); Co-IP and ubiquitination assays (Cul3-SPOP); ChIP, methylation-specific PCR, mutagenesis, and pharmacological inhibition (DNMT1 pathway)\",\n      \"pmids\": [\"21777593\", \"22085717\", \"21765477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of hexamerization in complex assembly unknown\", \"Additional E3 ligases targeting BRMS1 not yet surveyed\", \"Whether DNMT1-mediated silencing operates in all tumor types unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"BRMS1 was discovered to have intrinsic E3 ubiquitin ligase activity, targeting p300 for proteasomal degradation through a conserved CXD motif; this activity is essential for metastasis suppression, revealing a non-transcriptional effector mechanism.\",\n      \"evidence\": \"In vitro ubiquitination reconstitution, CXD motif mutagenesis, in vivo lung cancer metastasis model\",\n      \"pmids\": [\"23269275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether substrates beyond p300/CBP exist is unknown\", \"Structural basis of CXD-mediated E3 activity unresolved\", \"Relationship between E3 ligase function and mSin3 complex membership unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Functional dissection of BRMS1 localization signals revealed that the C-terminal NLS2 is dispensable for nuclear import but essential for metastasis suppression and SIN3A interaction in both compartments, and that BRMS1 suppresses integrin β1/FAK activation at focal adhesions to delay cell adhesion.\",\n      \"evidence\": \"NLS mutagenesis/truncation with xenograft metastasis assay and SIN3A co-IP (NLS2); confocal microscopy, integrin activation assays, 3D culture (integrin/FAK)\",\n      \"pmids\": [\"23390556\", \"24000122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking BRMS1 to integrin activation status unknown\", \"Whether cytoplasmic SIN3A complex has distinct gene targets is unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"BRMS1 was shown to suppress EMT by preventing NF-κB-dependent Twist1 transcription; loss of BRMS1 increased RelA/p65 K310 acetylation at the Twist1 promoter, connecting BRMS1's chromatin-remodeling role to the EMT program.\",\n      \"evidence\": \"shRNA knockdown, ChIP at Twist1 promoter, epistasis with Twist1 KD, in vivo lung tumor model\",\n      \"pmids\": [\"25368381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRMS1 directly deacetylates RelA K310 or acts indirectly unclear\", \"Contribution of EMT suppression relative to anoikis sensitization in vivo unquantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Two phosphorylation events regulating BRMS1 were mapped: CK2α′ phosphorylates S30 to trigger 14-3-3ε-mediated nuclear export and degradation (targetable by CX4945), while CDK2 phosphorylates S237 to regulate migration-related protein interactions without affecting mSin3 complex association.\",\n      \"evidence\": \"Site-directed mutagenesis (S30, S237), co-IP with 14-3-3ε, CK2 inhibitor CX4945, in vitro CDK2 kinase assay, in vivo orthotopic metastasis model\",\n      \"pmids\": [\"26980766\", \"26771717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full phosphoproteome of BRMS1 not mapped\", \"Whether S30 and S237 phosphorylation events are coordinated or independent unknown\", \"Therapeutic window of CK2 inhibition for BRMS1 stabilization not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"BRMS1's functional repertoire expanded beyond mSin3: it was identified as a component of the LSD1/CoREST corepressor complex co-regulating metastasis genes, and separately shown to promote FANCI/FANCD2 monoubiquitination for DNA interstrand crosslink repair; additionally, TRIM7 was identified as a second E3 ligase degrading BRMS1.\",\n      \"evidence\": \"AP-MS and RNA-seq with migration/invasion assays (LSD1/CoREST); Co-IP, domain mapping, ICL sensitivity in CRISPR-KO cells (FANCI); Co-IP, ubiquitination assay, PDX model (TRIM7)\",\n      \"pmids\": [\"30416854\", \"30365131\", \"32853985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LSD1/CoREST and mSin3 complexes have overlapping or distinct BRMS1-dependent target genes unknown\", \"Structural basis of BRMS1-FANCI interaction not resolved\", \"Relative contributions of SPOP vs TRIM7 to BRMS1 turnover in different tissues unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A naturally occurring SNP (BRMS1v2 A273V) was shown to abolish metastasis suppression by disrupting interaction with nuclear Src, derepressing c-fos/CEACAM6 transcription, which was therapeutically targetable with c-fos inhibitor T5224.\",\n      \"evidence\": \"NGS variant identification, co-IP (BRMS1v2–nuclear Src), xenograft and PDO intracardiac injection models, pharmacological rescue with T5224\",\n      \"pmids\": [\"36197962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Population frequency and penetrance of A273V not determined from this study\", \"Whether nuclear Src interaction is relevant to BRMS1v1 function unknown\", \"Structural basis of Src-BRMS1v2 interaction unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include how BRMS1 partitions between mSin3/HDAC, LSD1/CoREST, and other complexes; the full spectrum of E3 ligase substrates beyond p300/CBP; the structural basis for its dual corepressor-component and E3-ligase activities; and whether BRMS1-stabilizing strategies (CK2 or TRIM7 inhibition) can be translated therapeutically.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrative structural model of full-length BRMS1 in complex\", \"No genome-wide identification of direct BRMS1-bound chromatin sites (e.g., genome-wide ChIP-seq)\", \"Therapeutic applicability of BRMS1 stabilization not tested in clinical settings\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [12, 16]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 5, 15, 25]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 13, 18, 19]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 13, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 5, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 15, 25]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 12, 21]}\n    ],\n    \"complexes\": [\n      \"mSin3A/HDAC corepressor complex\",\n      \"LSD1/CoREST corepressor complex\"\n    ],\n    \"partners\": [\n      \"SIN3A\",\n      \"HDAC1\",\n      \"RBP1\",\n      \"SPOP\",\n      \"TRIM7\",\n      \"FANCI\",\n      \"KPNA5\",\n      \"EP300\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}