{"gene":"HOXB7","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1996,"finding":"HOXB7 directly transactivates the bFGF (basic fibroblast growth factor) gene by binding to one of five putative homeodomain binding sites in its promoter, as demonstrated by band-shift (EMSA) and cotransfection assays; antisense oligomers targeting HOXB7 mRNA abolished bFGF expression and inhibited melanoma cell proliferation.","method":"EMSA (band-shift assay), cotransfection/reporter assay, antisense oligonucleotide knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct DNA-binding demonstrated by EMSA, transcriptional activation confirmed by cotransfection reporter assay, functional consequence confirmed by antisense knockdown; replicated in subsequent studies","pmids":["8756643"],"is_preprint":false},{"year":1998,"finding":"Transduction of HOXB7 into SkBr3 breast carcinoma cells (negative for both HOXB7 and bFGF) induced bFGF expression, increased cell proliferation, reduced serum dependence, and enabled anchorage-independent growth; antisense oligomers to bFGF inhibited growth in low-serum conditions, confirming bFGF as a functional downstream target of HOXB7.","method":"Retroviral gene transduction, ELISA, antisense oligonucleotide inhibition, colony formation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function transduction plus specific downstream target rescue/inhibition; consistent with findings from the 1996 paper","pmids":["9681827"],"is_preprint":false},{"year":1999,"finding":"HOXB7 physically interacted with the coactivator CBP (CREB-binding protein) both in vitro and in vivo; this interaction required the N-terminal domain of HOXB7 and two C-terminal domains of CBP, and enhanced HOXB7 transactivation potential. Histone deacetylase inhibition (trichostatin A) further enhanced HOXB7 transcriptional activity, implicating acetylation/deacetylation in regulation of HOXB7 function.","method":"Co-immunoprecipitation (in vivo), in vitro binding assay, deletion mutagenesis, transient transfection reporter assay, pharmacological inhibition (TSA)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal in vitro and in vivo binding with domain-mapping mutagenesis, functional reporter assay; single lab but multiple orthogonal methods","pmids":["10435624"],"is_preprint":false},{"year":1999,"finding":"HOXB7 physically interacted in vitro with IκB-α; this interaction was mediated by IκB-α ankyrin repeats and C-terminal domain, and the HOXB7 N-terminal domain. IκB-α markedly increased HOXB7-dependent transcription from a reporter plasmid containing a homeodomain consensus-binding sequence, revealing a novel role for IκB-α as a positive regulator of HOX transcriptional activity.","method":"In vitro binding assay, transient transfection reporter assay, deletion mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro binding plus functional reporter assay, single lab, no in vivo confirmation of interaction","pmids":["10026139"],"is_preprint":false},{"year":1999,"finding":"Enforced expression of HOXB7 in human hematopoietic progenitor/stem cells (HPCs/HSCs) stimulated proliferation of primitive HPC and HSC subsets, expanded granulo-monocytic progenitors and their progeny, and promoted myeloid-restricted differentiation with sustained blast cell proliferation, suggesting a role in myeloid lineage commitment.","method":"Retroviral transduction into purified human HPCs/HSCs, HPP-CFC assay, LTC-IC assay, clonogenic assay, liquid suspension culture","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean gain-of-function with defined cellular phenotype using multiple hematopoietic readouts; single lab","pmids":["10208421"],"is_preprint":false},{"year":2001,"finding":"HOXB7 transduction into SkBr3 cells upregulated VEGF-A, GROα/MGSA, IL-8, angiopoietin-2, and MMP-9, while abrogating angiopoietin-1; HOXB7-transduced cells formed highly vascularized tumors in nude mice with increased CD31/CD34-positive vessels, establishing HOXB7 as a key regulator of the tumor angiogenic switch through multiple proangiogenic targets.","method":"Retroviral transduction, expression profiling, in vitro endothelial coculture/3D matrix assay, in vivo xenograft with CD31/CD34 immunostaining","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function with multiple molecular targets identified and in vivo vascular phenotype confirmed; builds on replicated bFGF finding","pmids":["11522651"],"is_preprint":false},{"year":2001,"finding":"Functional regions of HOXB7 critical for inhibiting myeloid differentiation of 32D cells include the Pbx-binding pentapeptide motif, the DNA-binding homeodomain, and internal N-terminal sequences. Conversely, mutations eliminating casein kinase II target sites, the glutamate-rich C-terminus, or the first 14 amino acids led to enhanced differentiation, indicating these domains negatively regulate HOXB7 activity.","method":"Site-directed mutagenesis, deletion constructs, retroviral transduction into 32D myeloid cells, G-CSF-induced differentiation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with defined cellular phenotypic readout; multiple domain-function relationships established in single study","pmids":["11290787"],"is_preprint":false},{"year":2003,"finding":"The HOXB7 promoter is regulated by direct binding of transcription factors NF-Y, YY1, Sp1/Sp3, and USF-1 to specific sites in a 1.9-kb 5' region; site-specific mutagenesis of these binding sites reduced HOXB7 gene expression by 55–78%, demonstrating functional necessity of these regulatory elements.","method":"Site-specific mutagenesis, cell transfection, reporter assay, electrophoretic mobility shift assay (EMSA)","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus functional reporter assay with multiple transcription factor binding sites validated; single lab, multiple orthogonal methods","pmids":["12697323"],"is_preprint":false},{"year":2006,"finding":"Ectopic expression of HOXB7 in MCF10A and MDCK epithelial cells induced epithelial-mesenchymal transition (EMT), characterized by loss of claudin 1, claudin 7, mislocalization of claudin 4 and E-cadherin, and gain of vimentin and α-smooth muscle actin. HOXB7 upregulated bFGF, activated Ras and RhoA, and increased phosphorylation of ERK1/2; effects were reversed by FGF receptor inhibitors, Ras-MAPK inhibitors, and HOXB7-specific siRNA.","method":"Gain-of-function expression in epithelial cell lines, immunofluorescence, Western blot, GTP-Ras/RhoA pull-down assay, pharmacological inhibition, siRNA knockdown, in vivo xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (gain-of-function, siRNA, pharmacological rescue), replicated in two cell lines, in vivo confirmation; consistent with prior mechanistic studies","pmids":["17018609"],"is_preprint":false},{"year":2007,"finding":"HOXB7 interacts with the DNA-dependent protein kinase holoenzyme components Ku70, Ku80, and DNA-PKcs, as well as PARP, identified by GST pull-down/affinity chromatography and confirmed by co-immunoprecipitation in vivo. HOXB7 expression enhanced non-homologous end-joining (NHEJ) DNA repair in vitro and in vivo; silencing HOXB7 reversed these effects, establishing HOXB7 as a novel regulator of DNA double-strand break repair.","method":"GST pull-down/affinity chromatography, co-immunoprecipitation, NHEJ repair assay in vitro and in vivo, siRNA knockdown","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical pull-down confirmed by co-IP, functional NHEJ assay with gain- and loss-of-function; multiple orthogonal methods, novel mechanistic finding","pmids":["17308091"],"is_preprint":false},{"year":2008,"finding":"In SkBr3/HOXB7 cells, HoxB7 regulates expression of TALE cofactors by increasing Pbx2 and Prep1 and decreasing Pbx1. A dominant-negative Pbx1 mutant (Pbx1NT) that sequesters Prep1 in the cytoplasm reduced the oncogenic activity of HoxB7 (less aggressive phenotype, increased apoptosis, decreased cycling, upregulation of p16 and p53), demonstrating functional requirement of HOX-TALE cofactor interaction for HOXB7 oncogenic activity.","method":"Retroviral transduction, dominant-negative mutant expression, in vitro invasion/proliferation assay, in vivo xenograft, flow cytometry, Western blot","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via dominant-negative mutant with multiple phenotypic readouts; single lab","pmids":["18378073"],"is_preprint":false},{"year":2008,"finding":"In MMTV-Hoxb7/HER-2/neu double-transgenic mice, Hoxb7 played a dual role: it delayed mammary tumor onset and reduced multiplicity, but accelerated tumor growth rate and increased lung metastasis frequency once tumors appeared, demonstrating context-dependent modulation of HER-2/neu-driven mammary tumorigenesis by Hoxb7 in vivo.","method":"Generation of MMTV-Hoxb7 transgenic mice, crossing with MMTV-HER-2/neu transgenic mice, tumor monitoring, lung metastasis analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined genetic model with quantitative in vivo phenotypic readouts (tumor onset, multiplicity, metastasis); rigorous in vivo design","pmids":["18463397"],"is_preprint":false},{"year":2010,"finding":"Loss of miR-196a expression in melanoma cells leads to increased HOXB7 mRNA and protein levels, which subsequently elevate Ets-1 activity by inducing bFGF; Ets-1 then induces BMP4 expression. BMP4 was identified as the major mediator of bFGF-induced migration in melanoma cells, establishing a miR-196a→HOXB7→bFGF→Ets-1→BMP4 signaling cascade.","method":"miRNA overexpression/knockdown, Western blot, reporter assay, migration assay, pharmacological inhibition","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway components tested with gain/loss of function; single lab","pmids":["20480203"],"is_preprint":false},{"year":2011,"finding":"HOXB7 overexpression in MCF-7 cells rendered them resistant to tamoxifen by upregulating EGFR through direct binding of HOXB7 to the EGFR promoter, enhancing transcriptional activity. Extended tamoxifen treatment progressively increased HOXB7 and EGFR expression, establishing a mechanistic link between HOXB7, EGFR upregulation, and acquired endocrine resistance.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, gain-of-function overexpression, Western blot, tamoxifen resistance assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct HOXB7 binding to EGFR promoter shown by ChIP and validated by luciferase reporter with mutagenesis; multiple orthogonal methods; consistent with prior mechanistic framework","pmids":["21690342"],"is_preprint":false},{"year":2012,"finding":"PARP-1 interacts with HOXB7 through the homeodomain of HOXB7 and the first zinc finger of PARP-1; upon binding, PARP-1 poly(ADP-ribosyl)ates HOXB7, reducing its transcriptional activity. Deletion of the evolutionarily conserved C-terminal glutamate-rich tail of HOXB7 dramatically attenuated ADP-ribosylation and rendered HOXB7 transcriptionally more active; poly(ADP-ribosyl)ation altered the DNA-binding activity of HOXB7 (and HOXA7) but not four other tested HOX proteins.","method":"Co-immunoprecipitation, GST pull-down, in vitro ADP-ribosylation assay, deletion mutagenesis, luciferase reporter assay, EMSA","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical interaction confirmed by pull-down and co-IP, post-translational modification directly demonstrated by in vitro assay, domain requirement established by mutagenesis, functional consequence confirmed by reporter and DNA-binding assay","pmids":["22844406"],"is_preprint":false},{"year":2013,"finding":"The HOXB7/PBX2 dimer acts as a positive transcriptional regulator of oncogenic miR-221 and miR-222 in melanoma; disruption of HOXB7/PBX2 dimers (using the peptide HXR9 that blocks HOX/PBX dimerization) reduces miR-221/222 transcription and elevates c-FOS expression (a direct miR-221/222 target), resulting in cell death. This defines a HOXB7/PBX2→miR-221&222→c-FOS regulatory link.","method":"Peptide antagonist (HXR9) treatment, miRNA expression analysis, reporter assay, Western blot, apoptosis assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological disruption of HOXB7/PBX2 dimer with defined downstream molecular consequences; single lab, multiple orthogonal methods","pmids":["23400877"],"is_preprint":false},{"year":2014,"finding":"HOXB7 directly binds and activates the TGFβ2 promoter, as shown by luciferase and ChIP assays. HOXB7-induced migration and invasion were reversed by TGFβ2 knockdown or pharmacological TGFβ signaling inhibition. HOXB7 overexpression also promoted tumor-associated macrophage recruitment and M2 polarization, mediated by TGFβ2, identifying a non-cell-autonomous mechanism of HOXB7-promoted metastasis.","method":"ChIP assay, luciferase reporter assay, siRNA knockdown, pharmacological inhibition, in vivo lung metastasis model, macrophage coculture","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct promoter binding by ChIP and luciferase, functional epistasis by knockdown and pharmacological inhibition, in vivo validation; multiple orthogonal methods","pmids":["25542862"],"is_preprint":false},{"year":2015,"finding":"HOXB7 physically interacts with ERα (estrogen receptor-α), and the HOXB7-ERα complex enhances transcription of multiple ERα target genes including HER2, as demonstrated by ChIP analysis. MYC, stabilized via EGFR-HER2-mediated phosphorylation, inhibits transcription of miR-196a (a HOXB7 repressor), thereby increasing HOXB7 and ER target gene expression, defining a MYC→miR-196a→HOXB7→ERα-HER2 signaling axis.","method":"Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, reporter assay, small-molecule MYC inhibitors, in vivo xenograft regression","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct physical interaction confirmed by ChIP-IP, multiple target genes validated, upstream/downstream pathway defined by pharmacological and genetic tools, in vivo confirmation","pmids":["26180042"],"is_preprint":false},{"year":2015,"finding":"HOXB7 binding sites on breast cancer cell chromatin were mapped genome-wide (1,504 sites in BT-474 cells) by ChIP-seq; 17 sites were validated by ChIP-qPCR in multiple cell lines. New direct target genes including CTNND2 and SCGB1D2 were identified based on proximity to HOXB7 binding sites and expression changes.","method":"ChIP-seq, ChIP-qPCR, gene expression analysis","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide chromatin binding mapped with site-level validation; target gene assignment based on proximity and expression correlation rather than direct functional assay","pmids":["26014856"],"is_preprint":false},{"year":2015,"finding":"In mesenchymal stromal/stem cells (MSCs), miR-196a upregulation during aging inversely correlated with HOXB7 expression; forced HOXB7 expression improved cell growth, reduced senescence, and improved osteogenesis linked to increased autocrine bFGF secretion, establishing HOXB7 as a regulator of MSC proliferation and osteogenic differentiation via bFGF.","method":"miRNA overexpression, forced HOXB7 expression, proliferation assay, senescence assay, osteogenic differentiation assay, ELISA for bFGF","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined phenotypic and molecular readouts; consistent with established HOXB7-bFGF axis; single lab","pmids":["25428821"],"is_preprint":false},{"year":2016,"finding":"HoxB7 stimulates ERK1/2 phosphorylation in pancreatic cancer cell protrusions; knockdown of HOXB7 decreased ERK1/2 phosphorylation, reduced peripheral actin structures and cell protrusions, and inhibited cell motility and invasiveness. HOXB7/ERK1/2 signaling selectively activated JNK and HSP27 phosphorylation to promote motility, demonstrating a non-transcriptional cytoplasmic signaling role for HOXB7 in regulating actin dynamics.","method":"siRNA knockdown, rescue expression, immunocytochemistry, Western blot (phospho-ERK, phospho-JNK, phospho-HSP27), motility/invasion assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with rescue confirmation, defined signaling pathway with phosphoprotein readouts; single lab, novel non-transcriptional mechanism","pmids":["28912272"],"is_preprint":false},{"year":2016,"finding":"HOXB7 knockdown in cutaneous squamous cell carcinoma (CSCC) cells inhibited migration and invasion and induced apoptosis via inactivation of the Wnt/β-catenin signaling pathway; co-immunoprecipitation demonstrated that endogenous HOXB7 binds to β-catenin, and HOXB7 regulated expression of downstream Wnt/β-catenin target genes.","method":"siRNA knockdown, co-immunoprecipitation, Western blot, transwell assay, xenograft in nude mice","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct HOXB7-β-catenin interaction confirmed by co-IP with functional pathway consequences; in vivo validation","pmids":["30067384"],"is_preprint":false},{"year":2016,"finding":"HOXB7 knockdown in colon cancer cells (HoxB7-overexpressing) stimulated DNA repair in a transcription-dependent manner requiring both the transactivation domain and the homeodomain (which mediates KU70/80 interaction), while Cdx2 inhibited DNA repair via a transcription-independent mechanism. In cells co-expressing both proteins, Cdx2 formed a molecular complex with HoxB7 and prevented it from recognizing its chromatin target, reducing HoxB7-driven DNA repair.","method":"Co-immunoprecipitation, DNA repair functional assay (etoposide treatment), domain deletion mutagenesis, gain/loss-of-function","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical interaction confirmed by co-IP, functional DNA repair assay with domain-mapping; single lab, multiple orthogonal methods","pmids":["26902420"],"is_preprint":false},{"year":2017,"finding":"HOXB7 was localized to cell protrusions of migrating pancreatic cancer cells as shown by immunocytochemistry; this cytoplasmic/protrusion localization was functionally linked to actin remodeling and cell motility, as HOXB7 knockdown reduced protrusions and motility, which were restored by rescue expression.","method":"Immunocytochemistry, siRNA knockdown, rescue construct transfection, motility assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by imaging tied to functional consequence via knockdown/rescue; single lab","pmids":["28912272"],"is_preprint":false},{"year":2019,"finding":"HOXB7 interacts with Ku70, Ku80, and DNA-PKcs in esophageal squamous cell carcinoma cells, confirmed by GST pull-down, co-immunoprecipitation, and immunofluorescent colocalization; HOXB7 knockdown reduced Ku70, Ku80, and DNA-PKcs expression and arrested cells in S phase, sensitizing cells to cisplatin. The HOX/PBX dimerization inhibitor HXR9 synergized with cisplatin, providing further functional evidence.","method":"GST pull-down, co-immunoprecipitation, immunofluorescent colocalization, siRNA knockdown, Western blot, cisplatin sensitivity assay, HXR9 peptide treatment","journal":"Thoracic cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical interaction methods (pull-down, co-IP, colocalization), functional consequence of knockdown established; replicates finding from PMID 17308091","pmids":["31568655"],"is_preprint":false},{"year":2020,"finding":"HOXB7 and β-catenin formed a functional complex in adipose-derived mesenchymal stem cells (ADMSCs), confirmed by immunoprecipitation; this complex modulated both osteogenesis and adipogenesis. miR-24 targeting of HOXB7 inhibited osteogenesis and promoted adipogenesis, effects partially reversed by HOXB7 overexpression, indicating the miR-24/HOXB7/β-catenin axis controls differentiation balance.","method":"Immunoprecipitation, miRNA overexpression/knockdown, luciferase reporter assay, osteogenic/adipogenic differentiation assay, in vivo calvarial defect model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein-protein interaction confirmed by IP, functional differentiation assays with in vivo validation; single lab, multiple methods","pmids":["32413244"],"is_preprint":false},{"year":2023,"finding":"HOXB7 overexpression in immortalized NMuMG mammary cells induced cellular transformation, tumorigenesis, and lung metastasis through activation of JAK-STAT signaling, identifying JAK-STAT pathway activation as a downstream mechanism of HOXB7-driven malignant transformation.","method":"Gain-of-function overexpression in NMuMG cells, transformation assay, in vivo tumorigenesis and metastasis assay, JAK-STAT pathway analysis","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined gain-of-function with in vitro and in vivo phenotypic readouts and pathway identification; single lab","pmids":["36659836"],"is_preprint":false},{"year":2024,"finding":"HOXB7 was identified as a key transcriptional regulator of PIGT (GPI transamidase subunit) in hepatocellular carcinoma, with HOXB7-induced PIGT upregulation promoting HCC progression through the Wnt/β-catenin pathway; validated in animal models.","method":"JASPAR transcription factor binding prediction, in vivo tumor model validation, gene expression analysis","journal":"Expert review of anticancer therapy","confidence":"Low","confidence_rationale":"Tier 3-4 / Weak — bioinformatics prediction with in vivo model validation; direct HOXB7-PIGT promoter binding not directly shown by ChIP or reporter in this abstract","pmids":["40808272"],"is_preprint":false},{"year":2024,"finding":"HOXB7 downregulation using siRNA enhanced HLA class II expression on tumor cells by decreasing MAPK phosphorylation, and MAPK inhibition augmented IFN-γ production by HOXB7-reactive CD4+ T cells, establishing a mechanistic link between HOXB7 expression, MAPK signaling, and tumor immune evasion.","method":"siRNA knockdown, Western blot (phospho-MAPK), flow cytometry (HLA-II), T cell cytokine assay, MAPK inhibitor treatment","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — knockdown with defined molecular phenotype (phospho-MAPK, HLA-II expression) plus pharmacological confirmation; single lab, limited mechanistic depth","pmids":["36285482"],"is_preprint":false},{"year":2021,"finding":"HOXB7 silencing in TNBC MDA-MB-468 cells reduced DNMT3B expression and decreased methylation of the CDH1 (E-cadherin) promoter, resulting in increased CDH1 expression. ChIP-qPCR in HOXB7-overexpressing cells showed enriched HOXB7 binding at CTNNB1, EGFR, FGF2, CDH1, DNMT3B, TGFB2, and COMMD7 loci, suggesting HOXB7 regulates CDH1 epigenetically via DNMT3B.","method":"siRNA knockdown, RT-PCR, Western blot, bisulfite sequencing (promoter methylation), ChIP-qPCR","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromatin binding by ChIP-qPCR combined with methylation and expression analysis; single lab, multiple orthogonal methods","pmids":["34680970"],"is_preprint":false},{"year":2012,"finding":"The adenovirus early protein E4orf6 was identified as a novel HoxB7-associated protein by yeast two-hybrid screening; HoxB7 knockdown led to inefficient adenoviral progeny production and reduced expression of multiple adenoviral promoters, demonstrating that HoxB7 activates adenoviral gene transcription.","method":"Yeast two-hybrid, HoxB7 knockdown cell line, viral replication assay, adenoviral promoter expression analysis","journal":"Journal of virology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid interaction plus knockdown phenotype; limited mechanistic depth and indirect relevance to canonical HOXB7 biology","pmids":["22553335"],"is_preprint":false},{"year":1993,"finding":"Cis-acting elements controlling A-P restricted Hoxb-7 expression are located within 3.5 kb proximal upstream sequences; deletion analysis revealed at least three cooperating cis-acting control elements. One element conferring Hox-like A-P expression boundaries acts in an orientation- and promoter-dependent manner. Additionally, control sequences of Hoxb-7 map within the 3' UTR of the neighboring Hoxb-8 gene, and Hoxb-7 control sequences modulate Hoxb-8 expression, suggesting cis-regulatory interactions between clustered Hox genes.","method":"Transgenic mice, promoter-reporter deletion analysis, in situ hybridization","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — transgenic reporter deletion analysis, multiple constructs tested; replicated in transgenic model; foundational promoter characterization","pmids":["8104144"],"is_preprint":false},{"year":1998,"finding":"In Hoxa7/Hoxb7 double-mutant mice, first and second rib defects occurred at higher penetrance and expressivity than in single Hoxb7−/− mutants, demonstrating functional genetic interaction between paralogous Hoxa7 and Hoxb7 genes in patterning the upper thoracic skeleton.","method":"Targeted gene disruption (knockout), skeletal analysis of single and double mutant mice","journal":"Mechanisms of development","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-mutant genetic epistasis in mice with defined skeletal phenotypic readout; classical developmental genetics approach","pmids":["9784603"],"is_preprint":false},{"year":1998,"finding":"Culturing mouse mammary epithelial cell lines (SCp2 and CID-9) on a basement membrane that induces a lactational phenotype turned off Hoxb-7 expression, demonstrating that extracellular matrix signaling modulates HOXB7 expression in mammary epithelial cells.","method":"Culture on basement membrane vs. inert substratum (polyHEMA), RT-PCR","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (RT-PCR), no downstream mechanistic follow-up; demonstrates ECM-dependent regulation of HOXB7 expression","pmids":["9620166"],"is_preprint":false}],"current_model":"HOXB7 is a homeodomain transcription factor that directly transactivates bFGF and multiple other target genes (EGFR, TGFβ2, HER2, miR-221/222) by binding their promoters; it physically interacts with co-regulators including CBP, IκB-α, ERα (forming an ERα cofactor complex), PARP-1 (which poly(ADP-ribosyl)ates and suppresses its activity), and the DNA repair complex (Ku70/Ku80/DNA-PKcs, enhancing NHEJ); it requires TALE cofactors (PBX2/PREP1) for full oncogenic activity; it promotes EMT via bFGF/Ras/RhoA/MAPK and TGFβ2/SMAD3 pathways, drives angiogenesis by upregulating VEGF-A, IL-8, MMP-9, and angiopoietin-2, and also exerts cytoplasmic functions by stimulating ERK1/2 phosphorylation in cell protrusions to promote actin remodeling and cell motility; upstream, its expression is repressed by miR-196a (controlled by MYC) and EZH2-mediated H3K27me3 at its promoter, and activated by NF-Y, YY1, Sp1/Sp3, and USF-1 transcription factors."},"narrative":{"mechanistic_narrative":"HOXB7 is a homeodomain transcription factor that acts as an oncogenic master regulator of growth-factor signaling, angiogenesis, and epithelial-mesenchymal transition, while also fulfilling a developmental patterning role in the Hox cluster [PMID:8756643, PMID:17018609, PMID:9784603]. Its founding activity is direct transactivation of the bFGF gene through homeodomain binding to its promoter, an axis required for melanoma proliferation and driving downstream Ras/RhoA/MAPK signaling and EMT in epithelial cells [PMID:8756643, PMID:9681827, PMID:17018609]. HOXB7 directly binds and activates a broad set of oncogenic promoters, including EGFR (conferring tamoxifen resistance), TGFβ2 (promoting invasion and M2 macrophage recruitment), and miR-221/222, and its genome-wide binding sites have been mapped by ChIP-seq in breast cancer chromatin [PMID:21690342, PMID:25542862, PMID:23400877, PMID:26014856]. Beyond transcription, HOXB7 coordinates the tumor angiogenic switch by upregulating VEGF-A, IL-8, MMP-9, and angiopoietin-2 [PMID:11522651], and stimulates DNA double-strand break repair by physically associating with the NHEJ machinery Ku70/Ku80/DNA-PKcs through its homeodomain [PMID:17308091, PMID:31568655]. Its transcriptional output is tuned by protein partners: CBP and IκB-α enhance its activity, while PARP-1 binds the homeodomain and poly(ADP-ribosyl)ates the C-terminal glutamate-rich tail to suppress DNA binding [PMID:10435624, PMID:10026139, PMID:22844406]. Full oncogenic activity requires TALE cofactors PBX2/PREP1 acting as dimerization partners [PMID:18378073, PMID:23400877], and HOXB7 additionally forms a complex with ERα to activate ERα/HER2 target genes [PMID:26180042]. A non-transcriptional cytoplasmic role localizes HOXB7 to cell protrusions where it stimulates ERK1/2 phosphorylation to remodel actin and drive motility [PMID:28912272]. In development, Hoxb7 patterns the upper thoracic skeleton in functional cooperation with the paralog Hoxa7 [PMID:9784603].","teleology":[{"year":1993,"claim":"Before its biochemical activity was known, the question was how Hoxb-7 achieves its spatially restricted expression; cis-regulatory dissection established that clustered Hox control elements direct its anterior-posterior boundaries.","evidence":"Transgenic mouse promoter-reporter deletion analysis with in situ hybridization","pmids":["8104144"],"confidence":"Medium","gaps":["Trans-acting factors binding these elements not identified here","Does not address protein function"]},{"year":1996,"claim":"The first direct molecular function was established by showing HOXB7 binds and transactivates the bFGF promoter, linking a homeodomain factor to a defined growth-factor target driving proliferation.","evidence":"EMSA, cotransfection reporter assay, and antisense knockdown in melanoma cells","pmids":["8756643"],"confidence":"High","gaps":["Other direct targets not yet mapped","In vivo relevance not tested"]},{"year":1998,"claim":"Gain-of-function in breast carcinoma cells confirmed bFGF as a functional downstream effector, establishing HOXB7 as a transforming factor that confers anchorage-independent growth and serum independence.","evidence":"Retroviral transduction of SkBr3 cells, ELISA, antisense, colony formation","pmids":["9681827"],"confidence":"High","gaps":["bFGF-independent functions not addressed","Cofactor requirements unknown"]},{"year":1998,"claim":"The question of whether HOXB7 has an endogenous developmental role was answered by double-mutant genetics showing it patterns the thoracic skeleton cooperatively with its paralog Hoxa7.","evidence":"Hoxa7/Hoxb7 knockout mice with skeletal phenotyping","pmids":["9784603"],"confidence":"High","gaps":["Molecular targets in skeletal patterning unidentified","Relationship to oncogenic targets unexplored"]},{"year":1999,"claim":"To explain how HOXB7 transactivation is potentiated, protein partners were sought; CBP and IκB-α were shown to bind the HOXB7 N-terminus and enhance its transcriptional output, with acetylation implicated as a regulatory layer.","evidence":"Co-IP/in vitro binding, domain-mapping mutagenesis, reporter assays, TSA treatment","pmids":["10435624","10026139"],"confidence":"Medium","gaps":["IκB-α interaction shown in vitro only","Endogenous stoichiometry and target-gene specificity not defined"]},{"year":1999,"claim":"Whether HOXB7 affects normal cell fate was tested in hematopoietic progenitors, showing it stimulates progenitor proliferation and myeloid-restricted differentiation.","evidence":"Retroviral transduction of human HPCs/HSCs with clonogenic and LTC-IC assays","pmids":["10208421"],"confidence":"Medium","gaps":["Transcriptional targets in hematopoiesis unidentified","Single lab"]},{"year":2001,"claim":"The mechanism by which HOXB7 promotes tumor vascularization was defined by showing it coordinately upregulates multiple proangiogenic factors and yields highly vascularized xenografts, identifying it as a regulator of the angiogenic switch.","evidence":"Retroviral transduction, expression profiling, endothelial coculture, in vivo xenograft with CD31/CD34 staining","pmids":["11522651"],"confidence":"High","gaps":["Direct promoter binding to angiogenic genes not all shown","Relative contribution of each target unresolved"]},{"year":2001,"claim":"Structure-function mapping defined which HOXB7 domains drive versus restrain its activity, including the Pbx-binding pentapeptide and homeodomain as positive elements and the glutamate-rich C-terminus as a negative regulator.","evidence":"Systematic mutagenesis in 32D myeloid cells with G-CSF differentiation readout","pmids":["11290787"],"confidence":"High","gaps":["Biochemical basis of negative regulation by C-terminus not yet explained","Phosphorylation site function inferred indirectly"]},{"year":2003,"claim":"The upstream control of HOXB7 levels was clarified by identifying the transcription factors that activate its promoter, defining the regulatory inputs that set HOXB7 expression.","evidence":"Site-specific mutagenesis, reporter assays, and EMSA across a 1.9-kb promoter","pmids":["12697323"],"confidence":"High","gaps":["Context-specific use of these sites in cancer not tested","Chromatin-level regulation not addressed"]},{"year":2006,"claim":"The cellular consequence of HOXB7 activity was elevated from proliferation to EMT, showing HOXB7 drives mesenchymal conversion through a bFGF/Ras/RhoA/MAPK cascade reversible by pathway inhibitors.","evidence":"Gain-of-function in MCF10A/MDCK, immunofluorescence, GTPase pull-downs, pharmacological and siRNA rescue, xenograft","pmids":["17018609"],"confidence":"High","gaps":["Direct transcriptional targets of EMT beyond bFGF not mapped","Reversibility in vivo not addressed"]},{"year":2007,"claim":"A transcription-independent function was uncovered by showing HOXB7 binds the Ku70/Ku80/DNA-PKcs/PARP machinery and enhances NHEJ, recasting it as a regulator of DNA double-strand break repair.","evidence":"GST pull-down, co-IP, NHEJ repair assays, siRNA knockdown","pmids":["17308091"],"confidence":"High","gaps":["Whether HOXB7 acts catalytically or as a scaffold unresolved","Effect on repair fidelity not measured"]},{"year":2008,"claim":"The cofactor requirement for oncogenicity was tested, demonstrating HOXB7 oncogenic activity depends on TALE partners by modulating Pbx2/Prep1/Pbx1 balance.","evidence":"Dominant-negative Pbx1 expression, invasion/proliferation assays, xenograft, flow cytometry","pmids":["18378073"],"confidence":"Medium","gaps":["Direct HOXB7-PBX2 binding not biochemically shown here","Target genes dependent on TALE cofactors not mapped"]},{"year":2008,"claim":"The in vivo role in HER-2/neu mammary tumorigenesis was defined as context-dependent, with Hoxb7 delaying onset but accelerating growth and metastasis.","evidence":"MMTV-Hoxb7 × MMTV-HER-2/neu double-transgenic mice with tumor and metastasis monitoring","pmids":["18463397"],"confidence":"High","gaps":["Molecular basis of the dual phenotype unresolved","Stage-specific effectors not identified"]},{"year":2010,"claim":"Upstream miRNA control was integrated with downstream signaling, defining a miR-196a→HOXB7→bFGF→Ets-1→BMP4 cascade governing melanoma migration.","evidence":"miRNA gain/loss-of-function, reporter and migration assays, pharmacological inhibition","pmids":["20480203"],"confidence":"Medium","gaps":["Direct vs indirect steps not all shown","Single lineage tested"]},{"year":2011,"claim":"A clinically relevant direct target was identified by showing HOXB7 binds the EGFR promoter to confer tamoxifen resistance, linking HOXB7 to acquired endocrine resistance.","evidence":"ChIP, luciferase reporter, gain-of-function, tamoxifen resistance assay","pmids":["21690342"],"confidence":"High","gaps":["Feedback between EGFR and HOXB7 not fully resolved","In vivo resistance not tested here"]},{"year":2012,"claim":"Post-translational regulation was established by showing PARP-1 poly(ADP-ribosyl)ates the HOXB7 C-terminal tail to suppress DNA binding, explaining the negative role of that domain.","evidence":"Co-IP, GST pull-down, in vitro ADP-ribosylation, deletion mutagenesis, reporter and EMSA","pmids":["22844406"],"confidence":"High","gaps":["Physiological triggers of PARylation unknown","Genome-wide effect on binding not measured"]},{"year":2012,"claim":"An unexpected virus-host link was found in which HoxB7 associates with adenovirus E4orf6 and activates adenoviral promoters, broadening its transcriptional repertoire.","evidence":"Yeast two-hybrid, knockdown, viral replication and promoter assays","pmids":["22553335"],"confidence":"Low","gaps":["Interaction by yeast two-hybrid not confirmed in mammalian cells","Relevance to endogenous biology unclear"]},{"year":2013,"claim":"The HOXB7/PBX2 dimer was shown to directly drive oncogenic miR-221/222 transcription, and disrupting the dimer triggered cell death, validating dimerization as a vulnerability.","evidence":"HXR9 peptide antagonist, miRNA and reporter assays, apoptosis assay","pmids":["23400877"],"confidence":"Medium","gaps":["Direct dimer binding to miR-221/222 promoter not shown by ChIP","Single melanoma context"]},{"year":2014,"claim":"A non-cell-autonomous metastatic mechanism was defined by showing HOXB7 directly activates TGFβ2 to drive invasion and recruit M2 macrophages.","evidence":"ChIP, luciferase, siRNA, pharmacological inhibition, lung metastasis model, macrophage coculture","pmids":["25542862"],"confidence":"High","gaps":["Other tumor-microenvironment effectors not mapped","Direct vs paracrine contributions not fully separated"]},{"year":2015,"claim":"Genome-wide HOXB7 chromatin occupancy was mapped, expanding the direct target catalog beyond candidate genes.","evidence":"ChIP-seq with ChIP-qPCR validation and expression analysis in breast cancer cells","pmids":["26014856"],"confidence":"Medium","gaps":["Target assignment by proximity, not functional assay","Cell-line-specific binding generality untested"]},{"year":2015,"claim":"An ERα-cofactor function was established by showing HOXB7 forms a complex with ERα to activate ERα/HER2 targets within a MYC→miR-196a→HOXB7→ERα-HER2 axis.","evidence":"ChIP, co-IP, reporter, MYC inhibitors, xenograft regression","pmids":["26180042"],"confidence":"High","gaps":["Structural basis of HOXB7-ERα complex unknown","Generality across ER+ subtypes untested"]},{"year":2015,"claim":"A non-malignant regulatory role was confirmed in mesenchymal stem cells, where HOXB7 sustains proliferation and osteogenesis via autocrine bFGF, extending the bFGF axis to stem-cell aging.","evidence":"Forced expression, proliferation/senescence/osteogenic assays, bFGF ELISA","pmids":["25428821"],"confidence":"Medium","gaps":["Direct targets in MSCs beyond bFGF unidentified","Single lab"]},{"year":2016,"claim":"A cytoplasmic, non-transcriptional function was demonstrated by localizing HOXB7 to cell protrusions where it stimulates ERK1/2 to remodel actin and drive motility.","evidence":"siRNA knockdown with rescue, immunocytochemistry, phosphoprotein Western blots, motility assays in pancreatic cancer cells","pmids":["28912272"],"confidence":"Medium","gaps":["Mechanism of ERK activation by cytoplasmic HOXB7 unknown","Direct partners in protrusions unidentified"]},{"year":2016,"claim":"A direct interaction with β-catenin was found, linking HOXB7 to Wnt/β-catenin signaling to promote squamous carcinoma invasion and survival.","evidence":"Co-IP, siRNA knockdown, transwell assay, xenograft","pmids":["30067384"],"confidence":"Medium","gaps":["Whether β-catenin alters HOXB7 transcriptional output or vice versa unresolved","Direct vs indirect target genes unclear"]},{"year":2016,"claim":"The interplay of HOXB7-driven DNA repair with antagonists was clarified by showing Cdx2 forms a complex with HoxB7 to block its chromatin recognition and dampen repair.","evidence":"Co-IP, etoposide DNA repair assay, domain deletion in colon cancer cells","pmids":["26902420"],"confidence":"Medium","gaps":["Generality of Cdx2 antagonism beyond colon untested","Structural basis of competition unknown"]},{"year":2019,"claim":"The HOXB7-NHEJ axis was independently replicated and extended to chemoresistance, showing HOXB7 supports Ku/DNA-PKcs expression and cisplatin resistance in esophageal carcinoma.","evidence":"GST pull-down, co-IP, colocalization, siRNA, cisplatin sensitivity, HXR9 treatment","pmids":["31568655"],"confidence":"Medium","gaps":["Whether HOXB7 transcriptionally controls Ku/DNA-PKcs or acts post-translationally not resolved","Single tumor type"]},{"year":2020,"claim":"The HOXB7-β-catenin complex was extended to stem-cell lineage choice, showing a miR-24/HOXB7/β-catenin axis balances osteogenesis and adipogenesis.","evidence":"Immunoprecipitation, miRNA gain/loss, luciferase, differentiation assays, calvarial defect model","pmids":["32413244"],"confidence":"Medium","gaps":["Direct target genes of the complex in MSCs unmapped","Single lab"]},{"year":2021,"claim":"An epigenetic mode of EMT control was defined, showing HOXB7 silences CDH1 via DNMT3B-mediated promoter methylation, with ChIP confirming occupancy at multiple oncogenic loci.","evidence":"siRNA knockdown, bisulfite sequencing, ChIP-qPCR in TNBC cells","pmids":["34680970"],"confidence":"Medium","gaps":["Whether DNMT3B is a direct HOXB7 target gene not fully resolved","Single TNBC line"]},{"year":2023,"claim":"A new downstream transforming pathway was identified, showing HOXB7 drives transformation and metastasis through JAK-STAT activation.","evidence":"Gain-of-function in NMuMG cells, transformation and metastasis assays, pathway analysis","pmids":["36659836"],"confidence":"Medium","gaps":["Direct link between HOXB7 transcription and JAK-STAT activation unestablished","Single model"]},{"year":2024,"claim":"An immune-evasion mechanism was defined, showing HOXB7 suppresses tumor HLA class II via MAPK signaling and limits CD4+ T cell IFN-γ responses.","evidence":"siRNA knockdown, phospho-MAPK Western blot, HLA-II flow cytometry, T cell cytokine assay, MAPK inhibitor","pmids":["36285482"],"confidence":"Medium","gaps":["Direct transcriptional targets bridging HOXB7 and MAPK unidentified","Single lab"]},{"year":null,"claim":"How HOXB7 partitions between its nuclear transcriptional, chromatin-modifying, DNA-repair, and cytoplasmic actin-remodeling roles within a single cell, and what governs this switch, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of HOXB7 cofactor complexes","Determinants of nuclear vs cytoplasmic localization unknown","Regulatory logic integrating its multiple functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,13,16,17,18,29]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,14,18,29]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[20]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,13,16,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[20,23]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[20,23]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,13,16,17,18]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9,24,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,20,26,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,11,13,16,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[31,32,4]}],"complexes":["HOXB7/PBX2 dimer","DNA-PK holoenzyme (Ku70/Ku80/DNA-PKcs)","HOXB7/ERα complex"],"partners":["CBP","NFKBIA","PARP1","XRCC6","XRCC5","PRKDC","ESR1","CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09629","full_name":"Homeobox protein Hox-B7","aliases":["Homeobox protein HHO.C1","Homeobox protein Hox-2C"],"length_aa":217,"mass_kda":24.0,"function":"Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P09629/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HOXB7","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HOXB7","total_profiled":1310},"omim":[{"mim_id":"618819","title":"PBX HOMEOBOX-INTERACTING PROTEIN 1; PBXIP1","url":"https://www.omim.org/entry/618819"},{"mim_id":"612557","title":"LEUKEMIA, CHRONIC LYMPHOCYTIC, SUSCEPTIBILITY TO, 3","url":"https://www.omim.org/entry/612557"},{"mim_id":"600831","title":"DEATH-ASSOCIATED PROTEIN KINASE 1; DAPK1","url":"https://www.omim.org/entry/600831"},{"mim_id":"176310","title":"PRE-B-CELL LEUKEMIA TRANSCRIPTION FACTOR 1; PBX1","url":"https://www.omim.org/entry/176310"},{"mim_id":"142972","title":"HOMEOBOX C6; HOXC6","url":"https://www.omim.org/entry/142972"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"epididymis","ntpm":127.6}],"url":"https://www.proteinatlas.org/search/HOXB7"},"hgnc":{"alias_symbol":[],"prev_symbol":["HOX2","HOX2C"]},"alphafold":{"accession":"P09629","domains":[{"cath_id":"1.10.10.60","chopping":"145-197","consensus_level":"high","plddt":97.3549,"start":145,"end":197}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09629","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09629-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09629-F1-predicted_aligned_error_v6.png","plddt_mean":63.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HOXB7","jax_strain_url":"https://www.jax.org/strain/search?query=HOXB7"},"sequence":{"accession":"P09629","fasta_url":"https://rest.uniprot.org/uniprotkb/P09629.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09629/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09629"}},"corpus_meta":[{"pmid":"24853421","id":"PMC_24853421","title":"P53-regulated 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     \"method\": \"EMSA (band-shift assay), cotransfection/reporter assay, antisense oligonucleotide knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct DNA-binding demonstrated by EMSA, transcriptional activation confirmed by cotransfection reporter assay, functional consequence confirmed by antisense knockdown; replicated in subsequent studies\",\n      \"pmids\": [\"8756643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Transduction of HOXB7 into SkBr3 breast carcinoma cells (negative for both HOXB7 and bFGF) induced bFGF expression, increased cell proliferation, reduced serum dependence, and enabled anchorage-independent growth; antisense oligomers to bFGF inhibited growth in low-serum conditions, confirming bFGF as a functional downstream target of HOXB7.\",\n      \"method\": \"Retroviral gene transduction, ELISA, antisense oligonucleotide inhibition, colony formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function transduction plus specific downstream target rescue/inhibition; consistent with findings from the 1996 paper\",\n      \"pmids\": [\"9681827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HOXB7 physically interacted with the coactivator CBP (CREB-binding protein) both in vitro and in vivo; this interaction required the N-terminal domain of HOXB7 and two C-terminal domains of CBP, and enhanced HOXB7 transactivation potential. Histone deacetylase inhibition (trichostatin A) further enhanced HOXB7 transcriptional activity, implicating acetylation/deacetylation in regulation of HOXB7 function.\",\n      \"method\": \"Co-immunoprecipitation (in vivo), in vitro binding assay, deletion mutagenesis, transient transfection reporter assay, pharmacological inhibition (TSA)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal in vitro and in vivo binding with domain-mapping mutagenesis, functional reporter assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10435624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HOXB7 physically interacted in vitro with IκB-α; this interaction was mediated by IκB-α ankyrin repeats and C-terminal domain, and the HOXB7 N-terminal domain. IκB-α markedly increased HOXB7-dependent transcription from a reporter plasmid containing a homeodomain consensus-binding sequence, revealing a novel role for IκB-α as a positive regulator of HOX transcriptional activity.\",\n      \"method\": \"In vitro binding assay, transient transfection reporter assay, deletion mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro binding plus functional reporter assay, single lab, no in vivo confirmation of interaction\",\n      \"pmids\": [\"10026139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Enforced expression of HOXB7 in human hematopoietic progenitor/stem cells (HPCs/HSCs) stimulated proliferation of primitive HPC and HSC subsets, expanded granulo-monocytic progenitors and their progeny, and promoted myeloid-restricted differentiation with sustained blast cell proliferation, suggesting a role in myeloid lineage commitment.\",\n      \"method\": \"Retroviral transduction into purified human HPCs/HSCs, HPP-CFC assay, LTC-IC assay, clonogenic assay, liquid suspension culture\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain-of-function with defined cellular phenotype using multiple hematopoietic readouts; single lab\",\n      \"pmids\": [\"10208421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HOXB7 transduction into SkBr3 cells upregulated VEGF-A, GROα/MGSA, IL-8, angiopoietin-2, and MMP-9, while abrogating angiopoietin-1; HOXB7-transduced cells formed highly vascularized tumors in nude mice with increased CD31/CD34-positive vessels, establishing HOXB7 as a key regulator of the tumor angiogenic switch through multiple proangiogenic targets.\",\n      \"method\": \"Retroviral transduction, expression profiling, in vitro endothelial coculture/3D matrix assay, in vivo xenograft with CD31/CD34 immunostaining\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function with multiple molecular targets identified and in vivo vascular phenotype confirmed; builds on replicated bFGF finding\",\n      \"pmids\": [\"11522651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Functional regions of HOXB7 critical for inhibiting myeloid differentiation of 32D cells include the Pbx-binding pentapeptide motif, the DNA-binding homeodomain, and internal N-terminal sequences. Conversely, mutations eliminating casein kinase II target sites, the glutamate-rich C-terminus, or the first 14 amino acids led to enhanced differentiation, indicating these domains negatively regulate HOXB7 activity.\",\n      \"method\": \"Site-directed mutagenesis, deletion constructs, retroviral transduction into 32D myeloid cells, G-CSF-induced differentiation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with defined cellular phenotypic readout; multiple domain-function relationships established in single study\",\n      \"pmids\": [\"11290787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The HOXB7 promoter is regulated by direct binding of transcription factors NF-Y, YY1, Sp1/Sp3, and USF-1 to specific sites in a 1.9-kb 5' region; site-specific mutagenesis of these binding sites reduced HOXB7 gene expression by 55–78%, demonstrating functional necessity of these regulatory elements.\",\n      \"method\": \"Site-specific mutagenesis, cell transfection, reporter assay, electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus functional reporter assay with multiple transcription factor binding sites validated; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12697323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ectopic expression of HOXB7 in MCF10A and MDCK epithelial cells induced epithelial-mesenchymal transition (EMT), characterized by loss of claudin 1, claudin 7, mislocalization of claudin 4 and E-cadherin, and gain of vimentin and α-smooth muscle actin. HOXB7 upregulated bFGF, activated Ras and RhoA, and increased phosphorylation of ERK1/2; effects were reversed by FGF receptor inhibitors, Ras-MAPK inhibitors, and HOXB7-specific siRNA.\",\n      \"method\": \"Gain-of-function expression in epithelial cell lines, immunofluorescence, Western blot, GTP-Ras/RhoA pull-down assay, pharmacological inhibition, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (gain-of-function, siRNA, pharmacological rescue), replicated in two cell lines, in vivo confirmation; consistent with prior mechanistic studies\",\n      \"pmids\": [\"17018609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOXB7 interacts with the DNA-dependent protein kinase holoenzyme components Ku70, Ku80, and DNA-PKcs, as well as PARP, identified by GST pull-down/affinity chromatography and confirmed by co-immunoprecipitation in vivo. HOXB7 expression enhanced non-homologous end-joining (NHEJ) DNA repair in vitro and in vivo; silencing HOXB7 reversed these effects, establishing HOXB7 as a novel regulator of DNA double-strand break repair.\",\n      \"method\": \"GST pull-down/affinity chromatography, co-immunoprecipitation, NHEJ repair assay in vitro and in vivo, siRNA knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical pull-down confirmed by co-IP, functional NHEJ assay with gain- and loss-of-function; multiple orthogonal methods, novel mechanistic finding\",\n      \"pmids\": [\"17308091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In SkBr3/HOXB7 cells, HoxB7 regulates expression of TALE cofactors by increasing Pbx2 and Prep1 and decreasing Pbx1. A dominant-negative Pbx1 mutant (Pbx1NT) that sequesters Prep1 in the cytoplasm reduced the oncogenic activity of HoxB7 (less aggressive phenotype, increased apoptosis, decreased cycling, upregulation of p16 and p53), demonstrating functional requirement of HOX-TALE cofactor interaction for HOXB7 oncogenic activity.\",\n      \"method\": \"Retroviral transduction, dominant-negative mutant expression, in vitro invasion/proliferation assay, in vivo xenograft, flow cytometry, Western blot\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via dominant-negative mutant with multiple phenotypic readouts; single lab\",\n      \"pmids\": [\"18378073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In MMTV-Hoxb7/HER-2/neu double-transgenic mice, Hoxb7 played a dual role: it delayed mammary tumor onset and reduced multiplicity, but accelerated tumor growth rate and increased lung metastasis frequency once tumors appeared, demonstrating context-dependent modulation of HER-2/neu-driven mammary tumorigenesis by Hoxb7 in vivo.\",\n      \"method\": \"Generation of MMTV-Hoxb7 transgenic mice, crossing with MMTV-HER-2/neu transgenic mice, tumor monitoring, lung metastasis analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined genetic model with quantitative in vivo phenotypic readouts (tumor onset, multiplicity, metastasis); rigorous in vivo design\",\n      \"pmids\": [\"18463397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of miR-196a expression in melanoma cells leads to increased HOXB7 mRNA and protein levels, which subsequently elevate Ets-1 activity by inducing bFGF; Ets-1 then induces BMP4 expression. BMP4 was identified as the major mediator of bFGF-induced migration in melanoma cells, establishing a miR-196a→HOXB7→bFGF→Ets-1→BMP4 signaling cascade.\",\n      \"method\": \"miRNA overexpression/knockdown, Western blot, reporter assay, migration assay, pharmacological inhibition\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway components tested with gain/loss of function; single lab\",\n      \"pmids\": [\"20480203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HOXB7 overexpression in MCF-7 cells rendered them resistant to tamoxifen by upregulating EGFR through direct binding of HOXB7 to the EGFR promoter, enhancing transcriptional activity. Extended tamoxifen treatment progressively increased HOXB7 and EGFR expression, establishing a mechanistic link between HOXB7, EGFR upregulation, and acquired endocrine resistance.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, gain-of-function overexpression, Western blot, tamoxifen resistance assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct HOXB7 binding to EGFR promoter shown by ChIP and validated by luciferase reporter with mutagenesis; multiple orthogonal methods; consistent with prior mechanistic framework\",\n      \"pmids\": [\"21690342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PARP-1 interacts with HOXB7 through the homeodomain of HOXB7 and the first zinc finger of PARP-1; upon binding, PARP-1 poly(ADP-ribosyl)ates HOXB7, reducing its transcriptional activity. Deletion of the evolutionarily conserved C-terminal glutamate-rich tail of HOXB7 dramatically attenuated ADP-ribosylation and rendered HOXB7 transcriptionally more active; poly(ADP-ribosyl)ation altered the DNA-binding activity of HOXB7 (and HOXA7) but not four other tested HOX proteins.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, in vitro ADP-ribosylation assay, deletion mutagenesis, luciferase reporter assay, EMSA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical interaction confirmed by pull-down and co-IP, post-translational modification directly demonstrated by in vitro assay, domain requirement established by mutagenesis, functional consequence confirmed by reporter and DNA-binding assay\",\n      \"pmids\": [\"22844406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The HOXB7/PBX2 dimer acts as a positive transcriptional regulator of oncogenic miR-221 and miR-222 in melanoma; disruption of HOXB7/PBX2 dimers (using the peptide HXR9 that blocks HOX/PBX dimerization) reduces miR-221/222 transcription and elevates c-FOS expression (a direct miR-221/222 target), resulting in cell death. This defines a HOXB7/PBX2→miR-221&222→c-FOS regulatory link.\",\n      \"method\": \"Peptide antagonist (HXR9) treatment, miRNA expression analysis, reporter assay, Western blot, apoptosis assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological disruption of HOXB7/PBX2 dimer with defined downstream molecular consequences; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23400877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HOXB7 directly binds and activates the TGFβ2 promoter, as shown by luciferase and ChIP assays. HOXB7-induced migration and invasion were reversed by TGFβ2 knockdown or pharmacological TGFβ signaling inhibition. HOXB7 overexpression also promoted tumor-associated macrophage recruitment and M2 polarization, mediated by TGFβ2, identifying a non-cell-autonomous mechanism of HOXB7-promoted metastasis.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, siRNA knockdown, pharmacological inhibition, in vivo lung metastasis model, macrophage coculture\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct promoter binding by ChIP and luciferase, functional epistasis by knockdown and pharmacological inhibition, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"25542862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HOXB7 physically interacts with ERα (estrogen receptor-α), and the HOXB7-ERα complex enhances transcription of multiple ERα target genes including HER2, as demonstrated by ChIP analysis. MYC, stabilized via EGFR-HER2-mediated phosphorylation, inhibits transcription of miR-196a (a HOXB7 repressor), thereby increasing HOXB7 and ER target gene expression, defining a MYC→miR-196a→HOXB7→ERα-HER2 signaling axis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, reporter assay, small-molecule MYC inhibitors, in vivo xenograft regression\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct physical interaction confirmed by ChIP-IP, multiple target genes validated, upstream/downstream pathway defined by pharmacological and genetic tools, in vivo confirmation\",\n      \"pmids\": [\"26180042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HOXB7 binding sites on breast cancer cell chromatin were mapped genome-wide (1,504 sites in BT-474 cells) by ChIP-seq; 17 sites were validated by ChIP-qPCR in multiple cell lines. New direct target genes including CTNND2 and SCGB1D2 were identified based on proximity to HOXB7 binding sites and expression changes.\",\n      \"method\": \"ChIP-seq, ChIP-qPCR, gene expression analysis\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide chromatin binding mapped with site-level validation; target gene assignment based on proximity and expression correlation rather than direct functional assay\",\n      \"pmids\": [\"26014856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In mesenchymal stromal/stem cells (MSCs), miR-196a upregulation during aging inversely correlated with HOXB7 expression; forced HOXB7 expression improved cell growth, reduced senescence, and improved osteogenesis linked to increased autocrine bFGF secretion, establishing HOXB7 as a regulator of MSC proliferation and osteogenic differentiation via bFGF.\",\n      \"method\": \"miRNA overexpression, forced HOXB7 expression, proliferation assay, senescence assay, osteogenic differentiation assay, ELISA for bFGF\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined phenotypic and molecular readouts; consistent with established HOXB7-bFGF axis; single lab\",\n      \"pmids\": [\"25428821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HoxB7 stimulates ERK1/2 phosphorylation in pancreatic cancer cell protrusions; knockdown of HOXB7 decreased ERK1/2 phosphorylation, reduced peripheral actin structures and cell protrusions, and inhibited cell motility and invasiveness. HOXB7/ERK1/2 signaling selectively activated JNK and HSP27 phosphorylation to promote motility, demonstrating a non-transcriptional cytoplasmic signaling role for HOXB7 in regulating actin dynamics.\",\n      \"method\": \"siRNA knockdown, rescue expression, immunocytochemistry, Western blot (phospho-ERK, phospho-JNK, phospho-HSP27), motility/invasion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with rescue confirmation, defined signaling pathway with phosphoprotein readouts; single lab, novel non-transcriptional mechanism\",\n      \"pmids\": [\"28912272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HOXB7 knockdown in cutaneous squamous cell carcinoma (CSCC) cells inhibited migration and invasion and induced apoptosis via inactivation of the Wnt/β-catenin signaling pathway; co-immunoprecipitation demonstrated that endogenous HOXB7 binds to β-catenin, and HOXB7 regulated expression of downstream Wnt/β-catenin target genes.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, Western blot, transwell assay, xenograft in nude mice\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct HOXB7-β-catenin interaction confirmed by co-IP with functional pathway consequences; in vivo validation\",\n      \"pmids\": [\"30067384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HOXB7 knockdown in colon cancer cells (HoxB7-overexpressing) stimulated DNA repair in a transcription-dependent manner requiring both the transactivation domain and the homeodomain (which mediates KU70/80 interaction), while Cdx2 inhibited DNA repair via a transcription-independent mechanism. In cells co-expressing both proteins, Cdx2 formed a molecular complex with HoxB7 and prevented it from recognizing its chromatin target, reducing HoxB7-driven DNA repair.\",\n      \"method\": \"Co-immunoprecipitation, DNA repair functional assay (etoposide treatment), domain deletion mutagenesis, gain/loss-of-function\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical interaction confirmed by co-IP, functional DNA repair assay with domain-mapping; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26902420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HOXB7 was localized to cell protrusions of migrating pancreatic cancer cells as shown by immunocytochemistry; this cytoplasmic/protrusion localization was functionally linked to actin remodeling and cell motility, as HOXB7 knockdown reduced protrusions and motility, which were restored by rescue expression.\",\n      \"method\": \"Immunocytochemistry, siRNA knockdown, rescue construct transfection, motility assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by imaging tied to functional consequence via knockdown/rescue; single lab\",\n      \"pmids\": [\"28912272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HOXB7 interacts with Ku70, Ku80, and DNA-PKcs in esophageal squamous cell carcinoma cells, confirmed by GST pull-down, co-immunoprecipitation, and immunofluorescent colocalization; HOXB7 knockdown reduced Ku70, Ku80, and DNA-PKcs expression and arrested cells in S phase, sensitizing cells to cisplatin. The HOX/PBX dimerization inhibitor HXR9 synergized with cisplatin, providing further functional evidence.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, immunofluorescent colocalization, siRNA knockdown, Western blot, cisplatin sensitivity assay, HXR9 peptide treatment\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical interaction methods (pull-down, co-IP, colocalization), functional consequence of knockdown established; replicates finding from PMID 17308091\",\n      \"pmids\": [\"31568655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HOXB7 and β-catenin formed a functional complex in adipose-derived mesenchymal stem cells (ADMSCs), confirmed by immunoprecipitation; this complex modulated both osteogenesis and adipogenesis. miR-24 targeting of HOXB7 inhibited osteogenesis and promoted adipogenesis, effects partially reversed by HOXB7 overexpression, indicating the miR-24/HOXB7/β-catenin axis controls differentiation balance.\",\n      \"method\": \"Immunoprecipitation, miRNA overexpression/knockdown, luciferase reporter assay, osteogenic/adipogenic differentiation assay, in vivo calvarial defect model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein-protein interaction confirmed by IP, functional differentiation assays with in vivo validation; single lab, multiple methods\",\n      \"pmids\": [\"32413244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HOXB7 overexpression in immortalized NMuMG mammary cells induced cellular transformation, tumorigenesis, and lung metastasis through activation of JAK-STAT signaling, identifying JAK-STAT pathway activation as a downstream mechanism of HOXB7-driven malignant transformation.\",\n      \"method\": \"Gain-of-function overexpression in NMuMG cells, transformation assay, in vivo tumorigenesis and metastasis assay, JAK-STAT pathway analysis\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined gain-of-function with in vitro and in vivo phenotypic readouts and pathway identification; single lab\",\n      \"pmids\": [\"36659836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HOXB7 was identified as a key transcriptional regulator of PIGT (GPI transamidase subunit) in hepatocellular carcinoma, with HOXB7-induced PIGT upregulation promoting HCC progression through the Wnt/β-catenin pathway; validated in animal models.\",\n      \"method\": \"JASPAR transcription factor binding prediction, in vivo tumor model validation, gene expression analysis\",\n      \"journal\": \"Expert review of anticancer therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3-4 / Weak — bioinformatics prediction with in vivo model validation; direct HOXB7-PIGT promoter binding not directly shown by ChIP or reporter in this abstract\",\n      \"pmids\": [\"40808272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HOXB7 downregulation using siRNA enhanced HLA class II expression on tumor cells by decreasing MAPK phosphorylation, and MAPK inhibition augmented IFN-γ production by HOXB7-reactive CD4+ T cells, establishing a mechanistic link between HOXB7 expression, MAPK signaling, and tumor immune evasion.\",\n      \"method\": \"siRNA knockdown, Western blot (phospho-MAPK), flow cytometry (HLA-II), T cell cytokine assay, MAPK inhibitor treatment\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — knockdown with defined molecular phenotype (phospho-MAPK, HLA-II expression) plus pharmacological confirmation; single lab, limited mechanistic depth\",\n      \"pmids\": [\"36285482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HOXB7 silencing in TNBC MDA-MB-468 cells reduced DNMT3B expression and decreased methylation of the CDH1 (E-cadherin) promoter, resulting in increased CDH1 expression. ChIP-qPCR in HOXB7-overexpressing cells showed enriched HOXB7 binding at CTNNB1, EGFR, FGF2, CDH1, DNMT3B, TGFB2, and COMMD7 loci, suggesting HOXB7 regulates CDH1 epigenetically via DNMT3B.\",\n      \"method\": \"siRNA knockdown, RT-PCR, Western blot, bisulfite sequencing (promoter methylation), ChIP-qPCR\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromatin binding by ChIP-qPCR combined with methylation and expression analysis; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34680970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The adenovirus early protein E4orf6 was identified as a novel HoxB7-associated protein by yeast two-hybrid screening; HoxB7 knockdown led to inefficient adenoviral progeny production and reduced expression of multiple adenoviral promoters, demonstrating that HoxB7 activates adenoviral gene transcription.\",\n      \"method\": \"Yeast two-hybrid, HoxB7 knockdown cell line, viral replication assay, adenoviral promoter expression analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid interaction plus knockdown phenotype; limited mechanistic depth and indirect relevance to canonical HOXB7 biology\",\n      \"pmids\": [\"22553335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Cis-acting elements controlling A-P restricted Hoxb-7 expression are located within 3.5 kb proximal upstream sequences; deletion analysis revealed at least three cooperating cis-acting control elements. One element conferring Hox-like A-P expression boundaries acts in an orientation- and promoter-dependent manner. Additionally, control sequences of Hoxb-7 map within the 3' UTR of the neighboring Hoxb-8 gene, and Hoxb-7 control sequences modulate Hoxb-8 expression, suggesting cis-regulatory interactions between clustered Hox genes.\",\n      \"method\": \"Transgenic mice, promoter-reporter deletion analysis, in situ hybridization\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic reporter deletion analysis, multiple constructs tested; replicated in transgenic model; foundational promoter characterization\",\n      \"pmids\": [\"8104144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"In Hoxa7/Hoxb7 double-mutant mice, first and second rib defects occurred at higher penetrance and expressivity than in single Hoxb7−/− mutants, demonstrating functional genetic interaction between paralogous Hoxa7 and Hoxb7 genes in patterning the upper thoracic skeleton.\",\n      \"method\": \"Targeted gene disruption (knockout), skeletal analysis of single and double mutant mice\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-mutant genetic epistasis in mice with defined skeletal phenotypic readout; classical developmental genetics approach\",\n      \"pmids\": [\"9784603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Culturing mouse mammary epithelial cell lines (SCp2 and CID-9) on a basement membrane that induces a lactational phenotype turned off Hoxb-7 expression, demonstrating that extracellular matrix signaling modulates HOXB7 expression in mammary epithelial cells.\",\n      \"method\": \"Culture on basement membrane vs. inert substratum (polyHEMA), RT-PCR\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (RT-PCR), no downstream mechanistic follow-up; demonstrates ECM-dependent regulation of HOXB7 expression\",\n      \"pmids\": [\"9620166\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOXB7 is a homeodomain transcription factor that directly transactivates bFGF and multiple other target genes (EGFR, TGFβ2, HER2, miR-221/222) by binding their promoters; it physically interacts with co-regulators including CBP, IκB-α, ERα (forming an ERα cofactor complex), PARP-1 (which poly(ADP-ribosyl)ates and suppresses its activity), and the DNA repair complex (Ku70/Ku80/DNA-PKcs, enhancing NHEJ); it requires TALE cofactors (PBX2/PREP1) for full oncogenic activity; it promotes EMT via bFGF/Ras/RhoA/MAPK and TGFβ2/SMAD3 pathways, drives angiogenesis by upregulating VEGF-A, IL-8, MMP-9, and angiopoietin-2, and also exerts cytoplasmic functions by stimulating ERK1/2 phosphorylation in cell protrusions to promote actin remodeling and cell motility; upstream, its expression is repressed by miR-196a (controlled by MYC) and EZH2-mediated H3K27me3 at its promoter, and activated by NF-Y, YY1, Sp1/Sp3, and USF-1 transcription factors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HOXB7 is a homeodomain transcription factor that acts as an oncogenic master regulator of growth-factor signaling, angiogenesis, and epithelial-mesenchymal transition, while also fulfilling a developmental patterning role in the Hox cluster [#0, #8, #32]. Its founding activity is direct transactivation of the bFGF gene through homeodomain binding to its promoter, an axis required for melanoma proliferation and driving downstream Ras/RhoA/MAPK signaling and EMT in epithelial cells [#0, #1, #8]. HOXB7 directly binds and activates a broad set of oncogenic promoters, including EGFR (conferring tamoxifen resistance), TGFβ2 (promoting invasion and M2 macrophage recruitment), and miR-221/222, and its genome-wide binding sites have been mapped by ChIP-seq in breast cancer chromatin [#13, #16, #15, #18]. Beyond transcription, HOXB7 coordinates the tumor angiogenic switch by upregulating VEGF-A, IL-8, MMP-9, and angiopoietin-2 [#5], and stimulates DNA double-strand break repair by physically associating with the NHEJ machinery Ku70/Ku80/DNA-PKcs through its homeodomain [#9, #24]. Its transcriptional output is tuned by protein partners: CBP and IκB-α enhance its activity, while PARP-1 binds the homeodomain and poly(ADP-ribosyl)ates the C-terminal glutamate-rich tail to suppress DNA binding [#2, #3, #14]. Full oncogenic activity requires TALE cofactors PBX2/PREP1 acting as dimerization partners [#10, #15], and HOXB7 additionally forms a complex with ERα to activate ERα/HER2 target genes [#17]. A non-transcriptional cytoplasmic role localizes HOXB7 to cell protrusions where it stimulates ERK1/2 phosphorylation to remodel actin and drive motility [#20, #23]. In development, Hoxb7 patterns the upper thoracic skeleton in functional cooperation with the paralog Hoxa7 [#32].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Before its biochemical activity was known, the question was how Hoxb-7 achieves its spatially restricted expression; cis-regulatory dissection established that clustered Hox control elements direct its anterior-posterior boundaries.\",\n      \"evidence\": \"Transgenic mouse promoter-reporter deletion analysis with in situ hybridization\",\n      \"pmids\": [\"8104144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-acting factors binding these elements not identified here\", \"Does not address protein function\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The first direct molecular function was established by showing HOXB7 binds and transactivates the bFGF promoter, linking a homeodomain factor to a defined growth-factor target driving proliferation.\",\n      \"evidence\": \"EMSA, cotransfection reporter assay, and antisense knockdown in melanoma cells\",\n      \"pmids\": [\"8756643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other direct targets not yet mapped\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Gain-of-function in breast carcinoma cells confirmed bFGF as a functional downstream effector, establishing HOXB7 as a transforming factor that confers anchorage-independent growth and serum independence.\",\n      \"evidence\": \"Retroviral transduction of SkBr3 cells, ELISA, antisense, colony formation\",\n      \"pmids\": [\"9681827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"bFGF-independent functions not addressed\", \"Cofactor requirements unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"The question of whether HOXB7 has an endogenous developmental role was answered by double-mutant genetics showing it patterns the thoracic skeleton cooperatively with its paralog Hoxa7.\",\n      \"evidence\": \"Hoxa7/Hoxb7 knockout mice with skeletal phenotyping\",\n      \"pmids\": [\"9784603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets in skeletal patterning unidentified\", \"Relationship to oncogenic targets unexplored\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"To explain how HOXB7 transactivation is potentiated, protein partners were sought; CBP and IκB-α were shown to bind the HOXB7 N-terminus and enhance its transcriptional output, with acetylation implicated as a regulatory layer.\",\n      \"evidence\": \"Co-IP/in vitro binding, domain-mapping mutagenesis, reporter assays, TSA treatment\",\n      \"pmids\": [\"10435624\", \"10026139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IκB-α interaction shown in vitro only\", \"Endogenous stoichiometry and target-gene specificity not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Whether HOXB7 affects normal cell fate was tested in hematopoietic progenitors, showing it stimulates progenitor proliferation and myeloid-restricted differentiation.\",\n      \"evidence\": \"Retroviral transduction of human HPCs/HSCs with clonogenic and LTC-IC assays\",\n      \"pmids\": [\"10208421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional targets in hematopoiesis unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The mechanism by which HOXB7 promotes tumor vascularization was defined by showing it coordinately upregulates multiple proangiogenic factors and yields highly vascularized xenografts, identifying it as a regulator of the angiogenic switch.\",\n      \"evidence\": \"Retroviral transduction, expression profiling, endothelial coculture, in vivo xenograft with CD31/CD34 staining\",\n      \"pmids\": [\"11522651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct promoter binding to angiogenic genes not all shown\", \"Relative contribution of each target unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Structure-function mapping defined which HOXB7 domains drive versus restrain its activity, including the Pbx-binding pentapeptide and homeodomain as positive elements and the glutamate-rich C-terminus as a negative regulator.\",\n      \"evidence\": \"Systematic mutagenesis in 32D myeloid cells with G-CSF differentiation readout\",\n      \"pmids\": [\"11290787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical basis of negative regulation by C-terminus not yet explained\", \"Phosphorylation site function inferred indirectly\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The upstream control of HOXB7 levels was clarified by identifying the transcription factors that activate its promoter, defining the regulatory inputs that set HOXB7 expression.\",\n      \"evidence\": \"Site-specific mutagenesis, reporter assays, and EMSA across a 1.9-kb promoter\",\n      \"pmids\": [\"12697323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-specific use of these sites in cancer not tested\", \"Chromatin-level regulation not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The cellular consequence of HOXB7 activity was elevated from proliferation to EMT, showing HOXB7 drives mesenchymal conversion through a bFGF/Ras/RhoA/MAPK cascade reversible by pathway inhibitors.\",\n      \"evidence\": \"Gain-of-function in MCF10A/MDCK, immunofluorescence, GTPase pull-downs, pharmacological and siRNA rescue, xenograft\",\n      \"pmids\": [\"17018609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of EMT beyond bFGF not mapped\", \"Reversibility in vivo not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A transcription-independent function was uncovered by showing HOXB7 binds the Ku70/Ku80/DNA-PKcs/PARP machinery and enhances NHEJ, recasting it as a regulator of DNA double-strand break repair.\",\n      \"evidence\": \"GST pull-down, co-IP, NHEJ repair assays, siRNA knockdown\",\n      \"pmids\": [\"17308091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HOXB7 acts catalytically or as a scaffold unresolved\", \"Effect on repair fidelity not measured\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The cofactor requirement for oncogenicity was tested, demonstrating HOXB7 oncogenic activity depends on TALE partners by modulating Pbx2/Prep1/Pbx1 balance.\",\n      \"evidence\": \"Dominant-negative Pbx1 expression, invasion/proliferation assays, xenograft, flow cytometry\",\n      \"pmids\": [\"18378073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HOXB7-PBX2 binding not biochemically shown here\", \"Target genes dependent on TALE cofactors not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The in vivo role in HER-2/neu mammary tumorigenesis was defined as context-dependent, with Hoxb7 delaying onset but accelerating growth and metastasis.\",\n      \"evidence\": \"MMTV-Hoxb7 × MMTV-HER-2/neu double-transgenic mice with tumor and metastasis monitoring\",\n      \"pmids\": [\"18463397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the dual phenotype unresolved\", \"Stage-specific effectors not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Upstream miRNA control was integrated with downstream signaling, defining a miR-196a→HOXB7→bFGF→Ets-1→BMP4 cascade governing melanoma migration.\",\n      \"evidence\": \"miRNA gain/loss-of-function, reporter and migration assays, pharmacological inhibition\",\n      \"pmids\": [\"20480203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect steps not all shown\", \"Single lineage tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A clinically relevant direct target was identified by showing HOXB7 binds the EGFR promoter to confer tamoxifen resistance, linking HOXB7 to acquired endocrine resistance.\",\n      \"evidence\": \"ChIP, luciferase reporter, gain-of-function, tamoxifen resistance assay\",\n      \"pmids\": [\"21690342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Feedback between EGFR and HOXB7 not fully resolved\", \"In vivo resistance not tested here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Post-translational regulation was established by showing PARP-1 poly(ADP-ribosyl)ates the HOXB7 C-terminal tail to suppress DNA binding, explaining the negative role of that domain.\",\n      \"evidence\": \"Co-IP, GST pull-down, in vitro ADP-ribosylation, deletion mutagenesis, reporter and EMSA\",\n      \"pmids\": [\"22844406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological triggers of PARylation unknown\", \"Genome-wide effect on binding not measured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"An unexpected virus-host link was found in which HoxB7 associates with adenovirus E4orf6 and activates adenoviral promoters, broadening its transcriptional repertoire.\",\n      \"evidence\": \"Yeast two-hybrid, knockdown, viral replication and promoter assays\",\n      \"pmids\": [\"22553335\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Interaction by yeast two-hybrid not confirmed in mammalian cells\", \"Relevance to endogenous biology unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The HOXB7/PBX2 dimer was shown to directly drive oncogenic miR-221/222 transcription, and disrupting the dimer triggered cell death, validating dimerization as a vulnerability.\",\n      \"evidence\": \"HXR9 peptide antagonist, miRNA and reporter assays, apoptosis assay\",\n      \"pmids\": [\"23400877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dimer binding to miR-221/222 promoter not shown by ChIP\", \"Single melanoma context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A non-cell-autonomous metastatic mechanism was defined by showing HOXB7 directly activates TGFβ2 to drive invasion and recruit M2 macrophages.\",\n      \"evidence\": \"ChIP, luciferase, siRNA, pharmacological inhibition, lung metastasis model, macrophage coculture\",\n      \"pmids\": [\"25542862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other tumor-microenvironment effectors not mapped\", \"Direct vs paracrine contributions not fully separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Genome-wide HOXB7 chromatin occupancy was mapped, expanding the direct target catalog beyond candidate genes.\",\n      \"evidence\": \"ChIP-seq with ChIP-qPCR validation and expression analysis in breast cancer cells\",\n      \"pmids\": [\"26014856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target assignment by proximity, not functional assay\", \"Cell-line-specific binding generality untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"An ERα-cofactor function was established by showing HOXB7 forms a complex with ERα to activate ERα/HER2 targets within a MYC→miR-196a→HOXB7→ERα-HER2 axis.\",\n      \"evidence\": \"ChIP, co-IP, reporter, MYC inhibitors, xenograft regression\",\n      \"pmids\": [\"26180042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of HOXB7-ERα complex unknown\", \"Generality across ER+ subtypes untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A non-malignant regulatory role was confirmed in mesenchymal stem cells, where HOXB7 sustains proliferation and osteogenesis via autocrine bFGF, extending the bFGF axis to stem-cell aging.\",\n      \"evidence\": \"Forced expression, proliferation/senescence/osteogenic assays, bFGF ELISA\",\n      \"pmids\": [\"25428821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct targets in MSCs beyond bFGF unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A cytoplasmic, non-transcriptional function was demonstrated by localizing HOXB7 to cell protrusions where it stimulates ERK1/2 to remodel actin and drive motility.\",\n      \"evidence\": \"siRNA knockdown with rescue, immunocytochemistry, phosphoprotein Western blots, motility assays in pancreatic cancer cells\",\n      \"pmids\": [\"28912272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ERK activation by cytoplasmic HOXB7 unknown\", \"Direct partners in protrusions unidentified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A direct interaction with β-catenin was found, linking HOXB7 to Wnt/β-catenin signaling to promote squamous carcinoma invasion and survival.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, transwell assay, xenograft\",\n      \"pmids\": [\"30067384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether β-catenin alters HOXB7 transcriptional output or vice versa unresolved\", \"Direct vs indirect target genes unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The interplay of HOXB7-driven DNA repair with antagonists was clarified by showing Cdx2 forms a complex with HoxB7 to block its chromatin recognition and dampen repair.\",\n      \"evidence\": \"Co-IP, etoposide DNA repair assay, domain deletion in colon cancer cells\",\n      \"pmids\": [\"26902420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of Cdx2 antagonism beyond colon untested\", \"Structural basis of competition unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The HOXB7-NHEJ axis was independently replicated and extended to chemoresistance, showing HOXB7 supports Ku/DNA-PKcs expression and cisplatin resistance in esophageal carcinoma.\",\n      \"evidence\": \"GST pull-down, co-IP, colocalization, siRNA, cisplatin sensitivity, HXR9 treatment\",\n      \"pmids\": [\"31568655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HOXB7 transcriptionally controls Ku/DNA-PKcs or acts post-translationally not resolved\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The HOXB7-β-catenin complex was extended to stem-cell lineage choice, showing a miR-24/HOXB7/β-catenin axis balances osteogenesis and adipogenesis.\",\n      \"evidence\": \"Immunoprecipitation, miRNA gain/loss, luciferase, differentiation assays, calvarial defect model\",\n      \"pmids\": [\"32413244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct target genes of the complex in MSCs unmapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"An epigenetic mode of EMT control was defined, showing HOXB7 silences CDH1 via DNMT3B-mediated promoter methylation, with ChIP confirming occupancy at multiple oncogenic loci.\",\n      \"evidence\": \"siRNA knockdown, bisulfite sequencing, ChIP-qPCR in TNBC cells\",\n      \"pmids\": [\"34680970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DNMT3B is a direct HOXB7 target gene not fully resolved\", \"Single TNBC line\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A new downstream transforming pathway was identified, showing HOXB7 drives transformation and metastasis through JAK-STAT activation.\",\n      \"evidence\": \"Gain-of-function in NMuMG cells, transformation and metastasis assays, pathway analysis\",\n      \"pmids\": [\"36659836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between HOXB7 transcription and JAK-STAT activation unestablished\", \"Single model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"An immune-evasion mechanism was defined, showing HOXB7 suppresses tumor HLA class II via MAPK signaling and limits CD4+ T cell IFN-γ responses.\",\n      \"evidence\": \"siRNA knockdown, phospho-MAPK Western blot, HLA-II flow cytometry, T cell cytokine assay, MAPK inhibitor\",\n      \"pmids\": [\"36285482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets bridging HOXB7 and MAPK unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HOXB7 partitions between its nuclear transcriptional, chromatin-modifying, DNA-repair, and cytoplasmic actin-remodeling roles within a single cell, and what governs this switch, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of HOXB7 cofactor complexes\", \"Determinants of nuclear vs cytoplasmic localization unknown\", \"Regulatory logic integrating its multiple functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 13, 16, 17, 18, 29]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 14, 18, 29]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 13, 16, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [20, 23]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [20, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 13, 16, 17, 18]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9, 24, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 20, 26, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 11, 13, 16, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [31, 32, 4]}\n    ],\n    \"complexes\": [\n      \"HOXB7/PBX2 dimer\",\n      \"DNA-PK holoenzyme (Ku70/Ku80/DNA-PKcs)\",\n      \"HOXB7/ERα complex\"\n    ],\n    \"partners\": [\n      \"CBP\",\n      \"NFKBIA\",\n      \"PARP1\",\n      \"XRCC6\",\n      \"XRCC5\",\n      \"PRKDC\",\n      \"ESR1\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}