{"gene":"CCNE1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1995,"finding":"Human cyclin E (CCNE1) gene maps to chromosome 19q12-->q13 by FISH, placing it near chromosomal regions involved in human tumors.","method":"Fluorescence in situ hybridization (FISH)","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal localization by FISH, replicated in a second independent paper (PMID:8833152)","pmids":["7698009","8833152"],"is_preprint":false},{"year":1996,"finding":"CCNE1 (cyclin E) localizes to chromosome 19q12 and interacts with cyclin-dependent kinases to facilitate G1/S phase entry.","method":"Chromosomal mapping; functional inference from cyclin-CDK biology confirmed by cloning","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromosomal localization confirmed by direct cloning; CDK interaction inferred from established cyclin biology; single lab","pmids":["8833152"],"is_preprint":false},{"year":2003,"finding":"Cyclin E overexpression in endometrial carcinoma is caused by CCNE1 gene amplification and, less frequently, by loss-of-function mutations in hCDC4 (FBXW7), the F-box protein that tags phosphorylated cyclin E for proteasomal degradation; one tumor with hCDC4 mutation also showed LOH at the locus.","method":"FISH for CCNE1 amplification; PCR-SSCP-sequencing for hCDC4 mutations; LOH analysis; immunohistochemistry","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (FISH, sequencing, IHC) in single lab; establishes two distinct mechanisms of CCNE1 overexpression","pmids":["14648662"],"is_preprint":false},{"year":2010,"finding":"CCNE1 is the key driver oncogene within the 19q12 amplicon: siRNA knockdown of CCNE1 (but not other genes in the amplicon) caused G1/S arrest, reduced viability, and apoptosis selectively in amplification-carrying ovarian cancer cells, and inhibited clonogenic survival after cisplatin treatment.","method":"siRNA knockdown; cell viability assay; flow cytometry (cell cycle/apoptosis); clonogenic survival assay; correlation of amplification with expression in primary tumors","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean gene-specific knockdown with amplicon-dependent phenotypic specificity; multiple orthogonal readouts; replicated across multiple cell lines","pmids":["21103391"],"is_preprint":false},{"year":2013,"finding":"CCNE1 amplification is synthetic lethal with BRCA1 loss: genome-wide shRNA screen identified BRCA1 and ubiquitin pathway members as selectively required in CCNE1-amplified cancer cells, providing a mechanistic explanation for the mutual exclusivity of CCNE1 amplification and BRCA1/2 mutation in high-grade serous ovarian cancer.","method":"Genome-wide shRNA synthetic lethal screen; proteasome inhibitor sensitivity assay (bortezomib)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-scale functional screen with pharmacological validation; explains mutual exclusivity observed in primary tumor data","pmids":["24218601"],"is_preprint":false},{"year":2013,"finding":"CDK2 is a therapeutic target downstream of CCNE1 amplification: selective sensitivity of CCNE1-amplified ovarian cancer cells to CDK2 knockdown or small-molecule CDK2 inhibitors was demonstrated; resistance emerged via CDK2 upregulation or selection of pre-existing polyploid cells.","method":"siRNA knockdown; small-molecule CDK2 inhibitors; FACS; gene expression and copy number analysis; karyotyping of resistant sublines","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and pharmacological validation; multiple orthogonal methods; amplicon-dependent selectivity demonstrated","pmids":["24004674"],"is_preprint":false},{"year":2016,"finding":"Induced expression of cyclin E1 in fallopian tube epithelial cells increased the percentage of cells showing centrosome amplification, directly linking CCNE1 overexpression to centrosome number abnormality.","method":"Ectopic expression of cyclin E1 in fallopian tube epithelial cells; centrosome counting","journal":"Modern pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gain-of-function experiment in primary cells; single lab; single method","pmids":["27443516"],"is_preprint":false},{"year":2019,"finding":"Cyclin E1 overexpression in mice (doxycycline-inducible Ccne1T model) caused incomplete DNA replication, centrosome amplification, non-perpendicular mitotic spindles, chromosome missegregation, aneuploidy, and polyploidization specifically in hepatocytes, leading to hepatocellular adenomas and HCCs.","method":"Doxycycline-inducible transgenic mouse model; MEF and hepatocyte analysis; chromosome counting; spindle angle measurement; tumor burden assessment","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with multiple orthogonal mechanistic readouts; tissue-specific phenotype explained mechanistically","pmids":["30878468"],"is_preprint":false},{"year":2019,"finding":"YAP1 positively regulates CCNE1 and CCNE2 expression by forming a complex with the transcription factor TEAD4; metformin disrupts this axis via AMPKα-mediated YAP1 inhibition, causing G1 cell cycle arrest in bladder cancer cells.","method":"Co-immunoprecipitation; dual-luciferase reporter assay; RNAi knockdown; Western blot; xenograft model; flow cytometry","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus luciferase validation; single lab; multiple orthogonal methods","pmids":["31455378"],"is_preprint":false},{"year":2019,"finding":"Genomic structural variations in gastric cancer cause enhancer hijacking at the CCNE1 locus: diverse distal enhancers are juxtaposed to CCNE1 proximal regions, disrupting TAD boundaries and creating novel TAD interactions, leading to high CCNE1 expression independent of gene amplification.","method":"Paired-end H3K27ac ChIP-seq; whole-genome sequencing; CRISPR/Cas9 editing; chromosome conformation capture (4C-seq, Capture-C); Hi-C","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal chromatin conformation and epigenomic methods; CRISPR functional validation; identifies non-amplification mechanism of CCNE1 overexpression","pmids":["31542774"],"is_preprint":false},{"year":2020,"finding":"METTL3, an m6A methyltransferase, stabilizes CCNE1 mRNA by methylating an m6A site in the 3'-UTR of CCNE1 mRNA, promoting colorectal cancer cell proliferation.","method":"m6A modification mapping; siRNA knockdown of METTL3; mRNA stability assay; cell proliferation assay; in vivo xenograft","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct m6A site identification with functional validation; single lab; mechanistic link established","pmids":["32039568"],"is_preprint":false},{"year":2022,"finding":"CCNE1 amplification engenders synthetic lethality with PKMYT1 kinase inhibition: increasing CCNE1 dosage activates the MMB-FOXM1 mitotic transcriptional program, disrupting CDK1 homeostasis; PKMYT1 inhibition (RP-6306) causes unscheduled CDK1 activation selectively in CCNE1-overexpressing cells, forcing early mitosis during S-phase and causing DNA damage and cell death.","method":"Genome-scale CRISPR-Cas9 synthetic lethality screen; selective PKMYT1 inhibitor (RP-6306) development; cell cycle and DNA synthesis assays; in vivo xenograft regressions; MMB-FOXM1 pathway analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — genome-scale CRISPR screen with pharmacological validation, mechanistic pathway dissection, and in vivo efficacy; replicated across multiple models","pmids":["35444283"],"is_preprint":false},{"year":2022,"finding":"KDM5B, a histone H3K4 demethylase, promotes CCNE1 protein accumulation in Ewing sarcoma by demethylating H3K4me3 at the FBXW7 promoter, thereby reducing FBXW7 transcription and blocking FBXW7-mediated ubiquitin-proteasomal degradation of CCNE1.","method":"KDM5B knockdown/overexpression; Western blot for CCNE1 protein and mRNA; ChIP for H3K4me3 at FBXW7 promoter; in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Western blot establish epigenetic mechanism; single lab; mRNA vs. protein distinction strengthens mechanistic claim","pmids":["35428764"],"is_preprint":false},{"year":2023,"finding":"CDK2, the canonical kinase partner of cyclin E1, uniquely regulates homologous recombination repair of collapsed replication forks in CCNE1-amplified ovarian cancer cells; CDK2 inhibition synergizes with DNA-damaging agents selectively in this genetic context.","method":"CRISPR whole-genome screens; CDK2 inhibitor treatment; replication fork collapse assays; HR repair assays; in vitro and in vivo combination studies","journal":"NAR cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-scale CRISPR screen plus targeted genetic/pharmacological validation; defines a specific CDK2 function unique to CCNE1-amplified context","pmids":["37519629"],"is_preprint":false},{"year":2025,"finding":"Combined PKMYT1 inhibition (RP-6306) and ATR inhibition (RP-3500) synergistically increases CDK1 activation, triggers premature mitosis, DNA damage, and apoptosis in a CCNE1-dependent manner, with durable antitumor activity in CCNE1-amplified patient-derived xenografts.","method":"Pharmacological combination studies; CDK1 activation assays; DNA damage markers (γH2AX); apoptosis assays; patient-derived xenograft models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection with multiple orthogonal methods; in vivo PDX validation; CCNE1-dependency confirmed genetically","pmids":["40169546"],"is_preprint":false},{"year":2021,"finding":"CCNE1 is synthetic lethal with ARID1A mutation in ovarian clear cell carcinoma: siRNA knockdown of CCNE1 selectively reduced proliferation in ARID1A-mutant cell lines but not in ARID1A wild-type lines, confirmed in vivo in xenograft models.","method":"siRNA screen for synthetic lethal partners of ARID1A; siRNA knockdown of CCNE1; cell proliferation assay; in vivo xenograft","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA screen plus isogenic cell line comparison and in vivo validation; single lab","pmids":["34070839"],"is_preprint":false},{"year":2025,"finding":"A selective CDK2 PROTAC degrader co-depletes CDK2 and cyclin E1 protein, achieving complete RB phosphorylation suppression and antiproliferative activity with greater selectivity for CCNE1-amplified cells; co-depletion resensitizes palbociclib-adapted breast cancer cells to cell cycle blockade.","method":"PROTAC degrader; Western blot for CDK2 and cyclin E1 protein levels; RB phosphorylation assays; antiproliferative assays; palbociclib-resistant cell models; in vivo oral dosing","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein co-degradation demonstrated; functional consequences measured; single lab","pmids":["40250405"],"is_preprint":false},{"year":2025,"finding":"CCNE1 stabilizes ANLN (Anillin) protein in TNBC by competitively inhibiting FZR1-mediated ubiquitination of ANLN; CCNE1 physically interacts with ANLN, and mutation of the ANLN ubiquitination site abrogates CCNE1's regulatory effect, demonstrating a non-CDK substrate interaction of cyclin E1.","method":"Co-immunoprecipitation (CCNE1-ANLN interaction); ubiquitination assays; site-directed mutagenesis of ANLN ubiquitination site; knockdown/overexpression functional assays; in vivo xenograft","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis establishes direct protein interaction and mechanistic role; single lab","pmids":["40346052"],"is_preprint":false},{"year":2024,"finding":"AURKB promotes CCNE1 expression in colorectal cancer by triggering phosphorylation of histone H3 at serine 10 (pH3S10) in the CCNE1 promoter region, thereby epigenetically activating CCNE1 transcription.","method":"ChIP assay for pH3S10 at CCNE1 promoter; AURKB knockdown; Western blot; xenograft model; AURKB inhibitor (AZD1152)","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly links pH3S10 to CCNE1 promoter; pharmacological validation; single lab","pmids":["38713155"],"is_preprint":false},{"year":2021,"finding":"SENP1-mediated SUMOylation of HIF-1α upregulates STC1 expression, which in turn increases CCNE1 expression and promotes Wilms tumor cell malignancy; SENP1 knockdown inhibits cell viability and CCNE1 levels in vitro and in vivo.","method":"Gain- and loss-of-function assays; SUMOylation analysis; Western blot; xenograft tumor model; co-expression analysis","journal":"Molecular therapy oncolytics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect pathway (SENP1→HIF-1α SUMOylation→STC1→CCNE1); mechanistic link to CCNE1 is indirect; single lab, no direct CCNE1-focused experiment","pmids":["34820505"],"is_preprint":false},{"year":2021,"finding":"TCF7L2 transcription factor binds to MYLK-AS1 lncRNA and positively promotes CCNE1 transcription; MYLK-AS1 silencing reduces TCF7L2-driven CCNE1 expression, inhibiting nephroblastoma cell proliferation.","method":"RNA binding protein immunoprecipitation; ChIP; dual-luciferase reporter assay; gain/loss-of-function; xenograft","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — TCF7L2-CCNE1 transcriptional link shown by ChIP and luciferase, but MYLK-AS1 is a lncRNA intermediary; single lab","pmids":["33438217"],"is_preprint":false},{"year":2018,"finding":"MNX1 transcriptionally upregulates CCNE1 and CCNE2 by directly binding to their promoters, promoting G1-S transition in bladder cancer cells.","method":"Chromatin immunoprecipitation (ChIP) to MNX1 binding at CCNE1/CCNE2 promoters; RT-PCR; Western blot; knockdown/overexpression proliferation assays; in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP binding at CCNE1 promoter; functional consequence demonstrated; single lab","pmids":["30012177"],"is_preprint":false},{"year":2022,"finding":"CCNE1 overexpression disrupts CDK1 homeostasis at least in part through early activation of the MMB-FOXM1 mitotic transcriptional program, as demonstrated by transcriptional profiling in CCNE1-overexpressing cells.","method":"Transcriptional program analysis; CCNE1 dose-dependent gene expression profiling; CRISPR functional screens","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection within a larger CRISPR screen study; mechanism supported by transcriptional data but not fully reconstituted; single lab","pmids":["35444283"],"is_preprint":false},{"year":2021,"finding":"CCNE1 overexpression in CCNE1-amplified tumors leads to increased dependence on the mTOR, homologous recombination, and DNA checkpoint pathways; mTOR inhibitors downregulate HR/checkpoint genes in CCNE1-amplified cells and show selective efficacy, and overexpression of HR/checkpoint proteins (RAD51 or ATR) confers resistance to mTORi.","method":"TCGA pathway enrichment analysis; Interactome Mapping Analysis; mTOR inhibitor treatment; Western blot for HR genes; overexpression rescue experiments; in vivo xenograft","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiments (RAD51/ATR overexpression reversing mTORi effects) establish pathway dependency; single lab","pmids":["35732503"],"is_preprint":false},{"year":2021,"finding":"CCNE1 overexpression selectively drives sensitivity to WEE1 inhibition at S-phase entry: only upon CCNE1 induction does WEE1 inhibition perturb DNA synthesis at S-phase entry; adding ATR inhibition increases double-strand breaks during DNA synthesis in a CCNE1 copy-number-dependent manner.","method":"CCNE1 induction experiments; DNA synthesis assays (EdU); DSB markers (γH2AX); WEE1i and ATRi combination; patient-derived xenograft models","journal":"Cell reports. Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — CCNE1 induction directly shown to confer WEE1i-dependent S-phase perturbation; multiple orthogonal assays; PDX validation","pmids":["34622231"],"is_preprint":false}],"current_model":"CCNE1 encodes cyclin E1, which drives G1/S phase transition by binding CDK2 to phosphorylate RB and activate E2F transcription; when amplified or overexpressed, it disrupts CDK1 homeostasis (partly through MMB-FOXM1 program activation) and causes replication stress, incomplete DNA replication, centrosome amplification, and chromosome instability, rendering cells synthetically lethal with inhibition of PKMYT1 (which restrains CDK1), CDK2 (which uniquely repairs collapsed replication forks via homologous recombination in this context), WEE1/ATR, or BRCA1/ubiquitin pathway components; cyclin E1 protein levels are regulated post-translationally by FBXW7-mediated ubiquitination (counteracted by CCNE1 itself and by KDM5B-driven FBXW7 repression), by METTL3-dependent m6A stabilization of its mRNA, and by transcriptional activation via YAP1-TEAD4, MNX1, AURKB-mediated H3S10 phosphorylation at its promoter, and enhancer hijacking through structural genomic rearrangements."},"narrative":{"mechanistic_narrative":"CCNE1 encodes cyclin E1, the regulatory partner of CDK2 that drives the G1/S phase transition through RB phosphorylation, and it functions as a potent oncogene when its dosage is increased [PMID:8833152, PMID:40250405]. CCNE1 resides in the chromosome 19q12 amplicon and is the critical driver gene within it: amplicon-carrying ovarian cancer cells specifically depend on CCNE1 for proliferation and survival, undergoing G1/S arrest and apoptosis upon its knockdown [PMID:7698009, PMID:8833152, PMID:21103391]. Excess cyclin E1 generates a characteristic oncogenic state — incomplete DNA replication, centrosome amplification, aberrant mitotic spindles, chromosome missegregation, and aneuploidy — as shown in inducible mouse and primary cell models linking overexpression directly to genomic instability and tumorigenesis [PMID:27443516, PMID:30878468]. Mechanistically, high CCNE1 dosage activates the MMB-FOXM1 mitotic transcriptional program and disrupts CDK1 homeostasis, creating dependencies that underlie multiple synthetic-lethal vulnerabilities: inhibition of PKMYT1 triggers unscheduled CDK1 activation and premature mitosis selectively in CCNE1-overexpressing cells, an effect synergized by ATR inhibition, while WEE1 inhibition perturbs S-phase entry in a CCNE1 copy-number-dependent manner [PMID:35444283, PMID:40169546, PMID:34622231]. CCNE1 amplification is also synthetic lethal with BRCA1 loss and ARID1A mutation, and confers a unique requirement for CDK2-mediated homologous-recombination repair of collapsed replication forks and for the mTOR/HR/checkpoint axis [PMID:24218601, PMID:34070839, PMID:37519629, PMID:35732503]. Cyclin E1 abundance is tightly controlled post-translationally by FBXW7-mediated ubiquitin-proteasomal degradation, which is blunted by KDM5B-driven FBXW7 repression and by METTL3-dependent m6A stabilization of CCNE1 mRNA, and CCNE1 transcription is activated by YAP1-TEAD4, MNX1, AURKB-mediated H3S10 phosphorylation, and enhancer hijacking through structural genomic rearrangements [PMID:14648662, PMID:35428764, PMID:32039568, PMID:31455378, PMID:30012177, PMID:38713155, PMID:31542774]. Beyond its canonical CDK2 partnership, cyclin E1 also physically binds ANLN and stabilizes it by competitively blocking FZR1-mediated ubiquitination, indicating a non-CDK substrate interaction [PMID:40346052].","teleology":[{"year":1996,"claim":"Establishing where CCNE1 sits in the genome and that it engages cyclin-dependent kinases to drive G1/S entry framed it as both a positional candidate near tumor-associated loci and a core cell-cycle regulator.","evidence":"FISH and chromosomal mapping confirmed by cloning, placing CCNE1 at 19q12-q13","pmids":["7698009","8833152"],"confidence":"Medium","gaps":["CDK interaction inferred from cyclin biology rather than directly reconstituted here","no functional consequence of the chromosomal location demonstrated yet"]},{"year":2003,"claim":"Identifying two routes to cyclin E overexpression — CCNE1 amplification and loss of the FBXW7 degron ligase — defined how tumors elevate cyclin E1 transcriptionally/genomically versus post-translationally.","evidence":"FISH, sequencing, LOH analysis and IHC in endometrial carcinoma","pmids":["14648662"],"confidence":"Medium","gaps":["correlative tumor data, not a controlled perturbation of FBXW7 in defined cells","does not establish downstream oncogenic consequence of the overexpression"]},{"year":2010,"claim":"Pinpointing CCNE1 as the single essential driver within the 19q12 amplicon converted a broad copy-number event into a specific, druggable dependency.","evidence":"Gene-specific siRNA knockdown with amplicon-dependent viability, cell-cycle and clonogenic readouts in ovarian cancer cells","pmids":["21103391"],"confidence":"High","gaps":["mechanism connecting amplification to dependency not yet resolved","did not identify therapeutic vulnerabilities"]},{"year":2013,"claim":"Genome-scale screens revealed that CCNE1-amplified cells become dependent on BRCA1/ubiquitin pathway components and on CDK2, explaining the mutual exclusivity of CCNE1 amplification with BRCA1/2 mutation and nominating CDK2 as a downstream target.","evidence":"Genome-wide shRNA synthetic-lethal screens, CDK2 knockdown/inhibitors, and pharmacological validation","pmids":["24218601","24004674"],"confidence":"High","gaps":["molecular basis of the BRCA1 requirement not fully dissected","resistance via CDK2 upregulation/polyploidy limits durability"]},{"year":2019,"claim":"Gain-of-function models in fallopian tube cells and inducible mice demonstrated that cyclin E1 overexpression directly causes centrosome amplification, replication defects, chromosome missegregation and tumors, establishing genomic instability as the oncogenic mechanism.","evidence":"Ectopic expression in primary epithelial cells and a doxycycline-inducible Ccne1 transgenic mouse with chromosome and spindle analyses","pmids":["27443516","30878468"],"confidence":"High","gaps":["molecular trigger linking cyclin E1 to centrosome overduplication not defined","tissue specificity of the hepatocyte phenotype unexplained"]},{"year":2019,"claim":"Mapping multiple upstream inputs — YAP1-TEAD4 transcriptional activation, enhancer hijacking by structural rearrangements, and m6A mRNA stabilization — showed that tumors elevate CCNE1 through diverse amplification-independent mechanisms.","evidence":"Co-IP/luciferase for YAP1-TEAD4; H3K27ac ChIP-seq, WGS, Hi-C/4C and CRISPR for enhancer hijacking; m6A mapping and stability assays for METTL3","pmids":["31455378","31542774","32039568"],"confidence":"Medium","gaps":["relative contribution of each mechanism across tumor types unknown","individual studies are single-lab"]},{"year":2022,"claim":"Connecting CCNE1 dosage to MMB-FOXM1 program activation and CDK1 homeostasis disruption identified PKMYT1 as a synthetic-lethal target, since unscheduled CDK1 activation forces premature mitosis selectively in CCNE1-high cells.","evidence":"Genome-scale CRISPR synthetic-lethality screen, transcriptional profiling, and selective PKMYT1 inhibitor RP-6306 with in vivo regressions","pmids":["35444283"],"confidence":"High","gaps":["MMB-FOXM1/CDK1 axis supported by transcriptional data, not fully reconstituted","biomarkers distinguishing responders incomplete"]},{"year":2022,"claim":"FBXW7-CCNE1 turnover was shown to be epigenetically tunable: KDM5B demethylates H3K4me3 at the FBXW7 promoter to repress the ligase and thereby stabilize cyclin E1 protein.","evidence":"KDM5B knockdown/overexpression with ChIP for H3K4me3 at FBXW7 and CCNE1 protein/mRNA distinction in Ewing sarcoma","pmids":["35428764"],"confidence":"Medium","gaps":["single-lab, single-context demonstration","generality across other tumor types untested"]},{"year":2021,"claim":"Defining further context-specific dependencies — ARID1A-mutant synthetic lethality, mTOR/HR/checkpoint reliance, and CCNE1-driven WEE1i/ATRi sensitivity at S-phase entry — broadened the actionable vulnerability landscape of CCNE1-overexpressing tumors.","evidence":"siRNA synthetic-lethal screening, mTOR-inhibitor treatment with RAD51/ATR rescue, and CCNE1 induction with EdU/γH2AX and PDX validation","pmids":["34070839","35732503","34622231"],"confidence":"Medium","gaps":["overlap and hierarchy among these dependencies not resolved","several are single-lab findings"]},{"year":2023,"claim":"Assigning CDK2 a specific role in homologous-recombination repair of collapsed replication forks in CCNE1-amplified cells explained why CDK2 inhibition synergizes with DNA-damaging agents in this context.","evidence":"CRISPR whole-genome screens with replication-fork-collapse and HR-repair assays plus combination studies","pmids":["37519629"],"confidence":"High","gaps":["whether this CDK2 function is fully independent of its cyclin E1 G1/S role not resolved"]},{"year":2025,"claim":"Newer therapeutic strategies — PKMYT1+ATR co-inhibition and a CDK2 PROTAC that co-depletes CDK2 and cyclin E1 — translated the mechanistic dependencies into agents with CCNE1-selective efficacy, including resensitization of palbociclib-adapted cells.","evidence":"Pharmacological combination with CDK1-activation/γH2AX readouts in PDX, and a CDK2 PROTAC degrader with RB-phosphorylation and antiproliferative assays","pmids":["40169546","40250405"],"confidence":"High","gaps":["clinical durability and resistance mechanisms not established","PROTAC data single-lab"]},{"year":2025,"claim":"Discovery that cyclin E1 physically binds ANLN and protects it from FZR1-mediated ubiquitination revealed a CDK2-independent, substrate-stabilizing activity of cyclin E1.","evidence":"Co-IP, ubiquitination assays, and site-directed mutagenesis of the ANLN ubiquitination site in TNBC","pmids":["40346052"],"confidence":"Medium","gaps":["structural basis of the CCNE1-ANLN interaction unknown","whether CDK2 contributes to this function untested","single-lab finding"]},{"year":null,"claim":"How cyclin E1 dosage mechanistically couples to centrosome overduplication and replication-stress generation, and which of the many synthetic-lethal dependencies offers the most durable clinical window, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no reconstituted molecular pathway from cyclin E1 to centrosome amplification","relative therapeutic priority among PKMYT1, CDK2, WEE1/ATR, mTOR dependencies undefined","in vivo resistance mechanisms across modalities not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,16]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16,18]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,11,16]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,4,7]}],"complexes":["cyclin E1-CDK2 complex"],"partners":["CDK2","FBXW7","ANLN","RB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P24864","full_name":"G1/S-specific cyclin-E1","aliases":[],"length_aa":410,"mass_kda":47.1,"function":"Essential for the control of the cell cycle at the G1/S (start) transition","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P24864/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNE1","classification":"Not Classified","n_dependent_lines":118,"n_total_lines":1208,"dependency_fraction":0.09768211920529801},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDK2","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"DNAJC18","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CCNE1","total_profiled":1310},"omim":[{"mim_id":"620694","title":"TUBULIN TYROSINE LIGASE-LIKE 11; TTLL11","url":"https://www.omim.org/entry/620694"},{"mim_id":"620012","title":"DEVELOPMENTAL DELAY, HYPOTONIA, AND IMPAIRED LANGUAGE; DEDHIL","url":"https://www.omim.org/entry/620012"},{"mim_id":"619572","title":"MICRO RNA 15B; MIR15B","url":"https://www.omim.org/entry/619572"},{"mim_id":"618764","title":"CDK2-ASSOCIATED CULLIN DOMAIN-CONTAINING PROTEIN 1; CACUL1","url":"https://www.omim.org/entry/618764"},{"mim_id":"617288","title":"SERINE PEPTIDASE INHIBITOR, KAZAL-TYPE, 7; SPINK7","url":"https://www.omim.org/entry/617288"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/36305147","citation_count":5,"is_preprint":false},{"pmid":"35430569","id":"PMC_35430569","title":"Role of Genetic Variations in CDK2, CCNE1 and p27 in Prostate Cancer.","date":"2022","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/35430569","citation_count":5,"is_preprint":false},{"pmid":"34769053","id":"PMC_34769053","title":"CCNE1 and E2F1 Partially Suppress G1 Phase Arrest Caused by Spliceostatin A Treatment.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34769053","citation_count":5,"is_preprint":false},{"pmid":"31571090","id":"PMC_31571090","title":"CDKN2A, CDK1, and CCNE1 overexpression in sebaceous gland carcinoma of eyelid.","date":"2019","source":"International ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/31571090","citation_count":5,"is_preprint":false},{"pmid":"38564163","id":"PMC_38564163","title":"Copy number signatures and CCNE1 amplification reveal the involvement of replication stress in high-grade endometrial tumors oncogenesis.","date":"2024","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/38564163","citation_count":5,"is_preprint":false},{"pmid":"34485660","id":"PMC_34485660","title":"CCNE1 amplification among metastatic sites in patients with gynecologic high-grade serous carcinoma.","date":"2021","source":"Gynecologic oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/34485660","citation_count":5,"is_preprint":false},{"pmid":"40842600","id":"PMC_40842600","title":"Genomic instability and CCNE1 amplification as emerging biomarkers for stratifying high-grade serous ovarian cancer.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40842600","citation_count":4,"is_preprint":false},{"pmid":"37572218","id":"PMC_37572218","title":"PKMYT1: A Potential Target for CCNE1 Amplificated Colorectal 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cancers by combined inhibition of PKMYT1 and ATR.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/38410486","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56566,"output_tokens":5973,"usd":0.129646,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14744,"output_tokens":4475,"usd":0.092798,"stage2_stop_reason":"end_turn"},"total_usd":0.222444,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Human cyclin E (CCNE1) gene maps to chromosome 19q12-->q13 by FISH, placing it near chromosomal regions involved in human tumors.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal localization by FISH, replicated in a second independent paper (PMID:8833152)\",\n      \"pmids\": [\"7698009\", \"8833152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CCNE1 (cyclin E) localizes to chromosome 19q12 and interacts with cyclin-dependent kinases to facilitate G1/S phase entry.\",\n      \"method\": \"Chromosomal mapping; functional inference from cyclin-CDK biology confirmed by cloning\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromosomal localization confirmed by direct cloning; CDK interaction inferred from established cyclin biology; single lab\",\n      \"pmids\": [\"8833152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cyclin E overexpression in endometrial carcinoma is caused by CCNE1 gene amplification and, less frequently, by loss-of-function mutations in hCDC4 (FBXW7), the F-box protein that tags phosphorylated cyclin E for proteasomal degradation; one tumor with hCDC4 mutation also showed LOH at the locus.\",\n      \"method\": \"FISH for CCNE1 amplification; PCR-SSCP-sequencing for hCDC4 mutations; LOH analysis; immunohistochemistry\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (FISH, sequencing, IHC) in single lab; establishes two distinct mechanisms of CCNE1 overexpression\",\n      \"pmids\": [\"14648662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCNE1 is the key driver oncogene within the 19q12 amplicon: siRNA knockdown of CCNE1 (but not other genes in the amplicon) caused G1/S arrest, reduced viability, and apoptosis selectively in amplification-carrying ovarian cancer cells, and inhibited clonogenic survival after cisplatin treatment.\",\n      \"method\": \"siRNA knockdown; cell viability assay; flow cytometry (cell cycle/apoptosis); clonogenic survival assay; correlation of amplification with expression in primary tumors\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean gene-specific knockdown with amplicon-dependent phenotypic specificity; multiple orthogonal readouts; replicated across multiple cell lines\",\n      \"pmids\": [\"21103391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCNE1 amplification is synthetic lethal with BRCA1 loss: genome-wide shRNA screen identified BRCA1 and ubiquitin pathway members as selectively required in CCNE1-amplified cancer cells, providing a mechanistic explanation for the mutual exclusivity of CCNE1 amplification and BRCA1/2 mutation in high-grade serous ovarian cancer.\",\n      \"method\": \"Genome-wide shRNA synthetic lethal screen; proteasome inhibitor sensitivity assay (bortezomib)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-scale functional screen with pharmacological validation; explains mutual exclusivity observed in primary tumor data\",\n      \"pmids\": [\"24218601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDK2 is a therapeutic target downstream of CCNE1 amplification: selective sensitivity of CCNE1-amplified ovarian cancer cells to CDK2 knockdown or small-molecule CDK2 inhibitors was demonstrated; resistance emerged via CDK2 upregulation or selection of pre-existing polyploid cells.\",\n      \"method\": \"siRNA knockdown; small-molecule CDK2 inhibitors; FACS; gene expression and copy number analysis; karyotyping of resistant sublines\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and pharmacological validation; multiple orthogonal methods; amplicon-dependent selectivity demonstrated\",\n      \"pmids\": [\"24004674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Induced expression of cyclin E1 in fallopian tube epithelial cells increased the percentage of cells showing centrosome amplification, directly linking CCNE1 overexpression to centrosome number abnormality.\",\n      \"method\": \"Ectopic expression of cyclin E1 in fallopian tube epithelial cells; centrosome counting\",\n      \"journal\": \"Modern pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gain-of-function experiment in primary cells; single lab; single method\",\n      \"pmids\": [\"27443516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cyclin E1 overexpression in mice (doxycycline-inducible Ccne1T model) caused incomplete DNA replication, centrosome amplification, non-perpendicular mitotic spindles, chromosome missegregation, aneuploidy, and polyploidization specifically in hepatocytes, leading to hepatocellular adenomas and HCCs.\",\n      \"method\": \"Doxycycline-inducible transgenic mouse model; MEF and hepatocyte analysis; chromosome counting; spindle angle measurement; tumor burden assessment\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with multiple orthogonal mechanistic readouts; tissue-specific phenotype explained mechanistically\",\n      \"pmids\": [\"30878468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YAP1 positively regulates CCNE1 and CCNE2 expression by forming a complex with the transcription factor TEAD4; metformin disrupts this axis via AMPKα-mediated YAP1 inhibition, causing G1 cell cycle arrest in bladder cancer cells.\",\n      \"method\": \"Co-immunoprecipitation; dual-luciferase reporter assay; RNAi knockdown; Western blot; xenograft model; flow cytometry\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus luciferase validation; single lab; multiple orthogonal methods\",\n      \"pmids\": [\"31455378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Genomic structural variations in gastric cancer cause enhancer hijacking at the CCNE1 locus: diverse distal enhancers are juxtaposed to CCNE1 proximal regions, disrupting TAD boundaries and creating novel TAD interactions, leading to high CCNE1 expression independent of gene amplification.\",\n      \"method\": \"Paired-end H3K27ac ChIP-seq; whole-genome sequencing; CRISPR/Cas9 editing; chromosome conformation capture (4C-seq, Capture-C); Hi-C\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal chromatin conformation and epigenomic methods; CRISPR functional validation; identifies non-amplification mechanism of CCNE1 overexpression\",\n      \"pmids\": [\"31542774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"METTL3, an m6A methyltransferase, stabilizes CCNE1 mRNA by methylating an m6A site in the 3'-UTR of CCNE1 mRNA, promoting colorectal cancer cell proliferation.\",\n      \"method\": \"m6A modification mapping; siRNA knockdown of METTL3; mRNA stability assay; cell proliferation assay; in vivo xenograft\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct m6A site identification with functional validation; single lab; mechanistic link established\",\n      \"pmids\": [\"32039568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCNE1 amplification engenders synthetic lethality with PKMYT1 kinase inhibition: increasing CCNE1 dosage activates the MMB-FOXM1 mitotic transcriptional program, disrupting CDK1 homeostasis; PKMYT1 inhibition (RP-6306) causes unscheduled CDK1 activation selectively in CCNE1-overexpressing cells, forcing early mitosis during S-phase and causing DNA damage and cell death.\",\n      \"method\": \"Genome-scale CRISPR-Cas9 synthetic lethality screen; selective PKMYT1 inhibitor (RP-6306) development; cell cycle and DNA synthesis assays; in vivo xenograft regressions; MMB-FOXM1 pathway analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genome-scale CRISPR screen with pharmacological validation, mechanistic pathway dissection, and in vivo efficacy; replicated across multiple models\",\n      \"pmids\": [\"35444283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM5B, a histone H3K4 demethylase, promotes CCNE1 protein accumulation in Ewing sarcoma by demethylating H3K4me3 at the FBXW7 promoter, thereby reducing FBXW7 transcription and blocking FBXW7-mediated ubiquitin-proteasomal degradation of CCNE1.\",\n      \"method\": \"KDM5B knockdown/overexpression; Western blot for CCNE1 protein and mRNA; ChIP for H3K4me3 at FBXW7 promoter; in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Western blot establish epigenetic mechanism; single lab; mRNA vs. protein distinction strengthens mechanistic claim\",\n      \"pmids\": [\"35428764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDK2, the canonical kinase partner of cyclin E1, uniquely regulates homologous recombination repair of collapsed replication forks in CCNE1-amplified ovarian cancer cells; CDK2 inhibition synergizes with DNA-damaging agents selectively in this genetic context.\",\n      \"method\": \"CRISPR whole-genome screens; CDK2 inhibitor treatment; replication fork collapse assays; HR repair assays; in vitro and in vivo combination studies\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-scale CRISPR screen plus targeted genetic/pharmacological validation; defines a specific CDK2 function unique to CCNE1-amplified context\",\n      \"pmids\": [\"37519629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Combined PKMYT1 inhibition (RP-6306) and ATR inhibition (RP-3500) synergistically increases CDK1 activation, triggers premature mitosis, DNA damage, and apoptosis in a CCNE1-dependent manner, with durable antitumor activity in CCNE1-amplified patient-derived xenografts.\",\n      \"method\": \"Pharmacological combination studies; CDK1 activation assays; DNA damage markers (γH2AX); apoptosis assays; patient-derived xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection with multiple orthogonal methods; in vivo PDX validation; CCNE1-dependency confirmed genetically\",\n      \"pmids\": [\"40169546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCNE1 is synthetic lethal with ARID1A mutation in ovarian clear cell carcinoma: siRNA knockdown of CCNE1 selectively reduced proliferation in ARID1A-mutant cell lines but not in ARID1A wild-type lines, confirmed in vivo in xenograft models.\",\n      \"method\": \"siRNA screen for synthetic lethal partners of ARID1A; siRNA knockdown of CCNE1; cell proliferation assay; in vivo xenograft\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen plus isogenic cell line comparison and in vivo validation; single lab\",\n      \"pmids\": [\"34070839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A selective CDK2 PROTAC degrader co-depletes CDK2 and cyclin E1 protein, achieving complete RB phosphorylation suppression and antiproliferative activity with greater selectivity for CCNE1-amplified cells; co-depletion resensitizes palbociclib-adapted breast cancer cells to cell cycle blockade.\",\n      \"method\": \"PROTAC degrader; Western blot for CDK2 and cyclin E1 protein levels; RB phosphorylation assays; antiproliferative assays; palbociclib-resistant cell models; in vivo oral dosing\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein co-degradation demonstrated; functional consequences measured; single lab\",\n      \"pmids\": [\"40250405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCNE1 stabilizes ANLN (Anillin) protein in TNBC by competitively inhibiting FZR1-mediated ubiquitination of ANLN; CCNE1 physically interacts with ANLN, and mutation of the ANLN ubiquitination site abrogates CCNE1's regulatory effect, demonstrating a non-CDK substrate interaction of cyclin E1.\",\n      \"method\": \"Co-immunoprecipitation (CCNE1-ANLN interaction); ubiquitination assays; site-directed mutagenesis of ANLN ubiquitination site; knockdown/overexpression functional assays; in vivo xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis establishes direct protein interaction and mechanistic role; single lab\",\n      \"pmids\": [\"40346052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AURKB promotes CCNE1 expression in colorectal cancer by triggering phosphorylation of histone H3 at serine 10 (pH3S10) in the CCNE1 promoter region, thereby epigenetically activating CCNE1 transcription.\",\n      \"method\": \"ChIP assay for pH3S10 at CCNE1 promoter; AURKB knockdown; Western blot; xenograft model; AURKB inhibitor (AZD1152)\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly links pH3S10 to CCNE1 promoter; pharmacological validation; single lab\",\n      \"pmids\": [\"38713155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SENP1-mediated SUMOylation of HIF-1α upregulates STC1 expression, which in turn increases CCNE1 expression and promotes Wilms tumor cell malignancy; SENP1 knockdown inhibits cell viability and CCNE1 levels in vitro and in vivo.\",\n      \"method\": \"Gain- and loss-of-function assays; SUMOylation analysis; Western blot; xenograft tumor model; co-expression analysis\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect pathway (SENP1→HIF-1α SUMOylation→STC1→CCNE1); mechanistic link to CCNE1 is indirect; single lab, no direct CCNE1-focused experiment\",\n      \"pmids\": [\"34820505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TCF7L2 transcription factor binds to MYLK-AS1 lncRNA and positively promotes CCNE1 transcription; MYLK-AS1 silencing reduces TCF7L2-driven CCNE1 expression, inhibiting nephroblastoma cell proliferation.\",\n      \"method\": \"RNA binding protein immunoprecipitation; ChIP; dual-luciferase reporter assay; gain/loss-of-function; xenograft\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — TCF7L2-CCNE1 transcriptional link shown by ChIP and luciferase, but MYLK-AS1 is a lncRNA intermediary; single lab\",\n      \"pmids\": [\"33438217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MNX1 transcriptionally upregulates CCNE1 and CCNE2 by directly binding to their promoters, promoting G1-S transition in bladder cancer cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) to MNX1 binding at CCNE1/CCNE2 promoters; RT-PCR; Western blot; knockdown/overexpression proliferation assays; in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP binding at CCNE1 promoter; functional consequence demonstrated; single lab\",\n      \"pmids\": [\"30012177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCNE1 overexpression disrupts CDK1 homeostasis at least in part through early activation of the MMB-FOXM1 mitotic transcriptional program, as demonstrated by transcriptional profiling in CCNE1-overexpressing cells.\",\n      \"method\": \"Transcriptional program analysis; CCNE1 dose-dependent gene expression profiling; CRISPR functional screens\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection within a larger CRISPR screen study; mechanism supported by transcriptional data but not fully reconstituted; single lab\",\n      \"pmids\": [\"35444283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCNE1 overexpression in CCNE1-amplified tumors leads to increased dependence on the mTOR, homologous recombination, and DNA checkpoint pathways; mTOR inhibitors downregulate HR/checkpoint genes in CCNE1-amplified cells and show selective efficacy, and overexpression of HR/checkpoint proteins (RAD51 or ATR) confers resistance to mTORi.\",\n      \"method\": \"TCGA pathway enrichment analysis; Interactome Mapping Analysis; mTOR inhibitor treatment; Western blot for HR genes; overexpression rescue experiments; in vivo xenograft\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiments (RAD51/ATR overexpression reversing mTORi effects) establish pathway dependency; single lab\",\n      \"pmids\": [\"35732503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCNE1 overexpression selectively drives sensitivity to WEE1 inhibition at S-phase entry: only upon CCNE1 induction does WEE1 inhibition perturb DNA synthesis at S-phase entry; adding ATR inhibition increases double-strand breaks during DNA synthesis in a CCNE1 copy-number-dependent manner.\",\n      \"method\": \"CCNE1 induction experiments; DNA synthesis assays (EdU); DSB markers (γH2AX); WEE1i and ATRi combination; patient-derived xenograft models\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CCNE1 induction directly shown to confer WEE1i-dependent S-phase perturbation; multiple orthogonal assays; PDX validation\",\n      \"pmids\": [\"34622231\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCNE1 encodes cyclin E1, which drives G1/S phase transition by binding CDK2 to phosphorylate RB and activate E2F transcription; when amplified or overexpressed, it disrupts CDK1 homeostasis (partly through MMB-FOXM1 program activation) and causes replication stress, incomplete DNA replication, centrosome amplification, and chromosome instability, rendering cells synthetically lethal with inhibition of PKMYT1 (which restrains CDK1), CDK2 (which uniquely repairs collapsed replication forks via homologous recombination in this context), WEE1/ATR, or BRCA1/ubiquitin pathway components; cyclin E1 protein levels are regulated post-translationally by FBXW7-mediated ubiquitination (counteracted by CCNE1 itself and by KDM5B-driven FBXW7 repression), by METTL3-dependent m6A stabilization of its mRNA, and by transcriptional activation via YAP1-TEAD4, MNX1, AURKB-mediated H3S10 phosphorylation at its promoter, and enhancer hijacking through structural genomic rearrangements.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCNE1 encodes cyclin E1, the regulatory partner of CDK2 that drives the G1/S phase transition through RB phosphorylation, and it functions as a potent oncogene when its dosage is increased [#1, #16]. CCNE1 resides in the chromosome 19q12 amplicon and is the critical driver gene within it: amplicon-carrying ovarian cancer cells specifically depend on CCNE1 for proliferation and survival, undergoing G1/S arrest and apoptosis upon its knockdown [#0, #3]. Excess cyclin E1 generates a characteristic oncogenic state — incomplete DNA replication, centrosome amplification, aberrant mitotic spindles, chromosome missegregation, and aneuploidy — as shown in inducible mouse and primary cell models linking overexpression directly to genomic instability and tumorigenesis [#6, #7]. Mechanistically, high CCNE1 dosage activates the MMB-FOXM1 mitotic transcriptional program and disrupts CDK1 homeostasis, creating dependencies that underlie multiple synthetic-lethal vulnerabilities: inhibition of PKMYT1 triggers unscheduled CDK1 activation and premature mitosis selectively in CCNE1-overexpressing cells, an effect synergized by ATR inhibition, while WEE1 inhibition perturbs S-phase entry in a CCNE1 copy-number-dependent manner [#11, #22, #14, #24]. CCNE1 amplification is also synthetic lethal with BRCA1 loss and ARID1A mutation, and confers a unique requirement for CDK2-mediated homologous-recombination repair of collapsed replication forks and for the mTOR/HR/checkpoint axis [#4, #15, #13, #23]. Cyclin E1 abundance is tightly controlled post-translationally by FBXW7-mediated ubiquitin-proteasomal degradation, which is blunted by KDM5B-driven FBXW7 repression and by METTL3-dependent m6A stabilization of CCNE1 mRNA, and CCNE1 transcription is activated by YAP1-TEAD4, MNX1, AURKB-mediated H3S10 phosphorylation, and enhancer hijacking through structural genomic rearrangements [#2, #12, #10, #8, #21, #18, #9]. Beyond its canonical CDK2 partnership, cyclin E1 also physically binds ANLN and stabilizes it by competitively blocking FZR1-mediated ubiquitination, indicating a non-CDK substrate interaction [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing where CCNE1 sits in the genome and that it engages cyclin-dependent kinases to drive G1/S entry framed it as both a positional candidate near tumor-associated loci and a core cell-cycle regulator.\",\n      \"evidence\": \"FISH and chromosomal mapping confirmed by cloning, placing CCNE1 at 19q12-q13\",\n      \"pmids\": [\"7698009\", \"8833152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CDK interaction inferred from cyclin biology rather than directly reconstituted here\", \"no functional consequence of the chromosomal location demonstrated yet\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying two routes to cyclin E overexpression — CCNE1 amplification and loss of the FBXW7 degron ligase — defined how tumors elevate cyclin E1 transcriptionally/genomically versus post-translationally.\",\n      \"evidence\": \"FISH, sequencing, LOH analysis and IHC in endometrial carcinoma\",\n      \"pmids\": [\"14648662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"correlative tumor data, not a controlled perturbation of FBXW7 in defined cells\", \"does not establish downstream oncogenic consequence of the overexpression\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Pinpointing CCNE1 as the single essential driver within the 19q12 amplicon converted a broad copy-number event into a specific, druggable dependency.\",\n      \"evidence\": \"Gene-specific siRNA knockdown with amplicon-dependent viability, cell-cycle and clonogenic readouts in ovarian cancer cells\",\n      \"pmids\": [\"21103391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism connecting amplification to dependency not yet resolved\", \"did not identify therapeutic vulnerabilities\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genome-scale screens revealed that CCNE1-amplified cells become dependent on BRCA1/ubiquitin pathway components and on CDK2, explaining the mutual exclusivity of CCNE1 amplification with BRCA1/2 mutation and nominating CDK2 as a downstream target.\",\n      \"evidence\": \"Genome-wide shRNA synthetic-lethal screens, CDK2 knockdown/inhibitors, and pharmacological validation\",\n      \"pmids\": [\"24218601\", \"24004674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular basis of the BRCA1 requirement not fully dissected\", \"resistance via CDK2 upregulation/polyploidy limits durability\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Gain-of-function models in fallopian tube cells and inducible mice demonstrated that cyclin E1 overexpression directly causes centrosome amplification, replication defects, chromosome missegregation and tumors, establishing genomic instability as the oncogenic mechanism.\",\n      \"evidence\": \"Ectopic expression in primary epithelial cells and a doxycycline-inducible Ccne1 transgenic mouse with chromosome and spindle analyses\",\n      \"pmids\": [\"27443516\", \"30878468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular trigger linking cyclin E1 to centrosome overduplication not defined\", \"tissue specificity of the hepatocyte phenotype unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapping multiple upstream inputs — YAP1-TEAD4 transcriptional activation, enhancer hijacking by structural rearrangements, and m6A mRNA stabilization — showed that tumors elevate CCNE1 through diverse amplification-independent mechanisms.\",\n      \"evidence\": \"Co-IP/luciferase for YAP1-TEAD4; H3K27ac ChIP-seq, WGS, Hi-C/4C and CRISPR for enhancer hijacking; m6A mapping and stability assays for METTL3\",\n      \"pmids\": [\"31455378\", \"31542774\", \"32039568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"relative contribution of each mechanism across tumor types unknown\", \"individual studies are single-lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connecting CCNE1 dosage to MMB-FOXM1 program activation and CDK1 homeostasis disruption identified PKMYT1 as a synthetic-lethal target, since unscheduled CDK1 activation forces premature mitosis selectively in CCNE1-high cells.\",\n      \"evidence\": \"Genome-scale CRISPR synthetic-lethality screen, transcriptional profiling, and selective PKMYT1 inhibitor RP-6306 with in vivo regressions\",\n      \"pmids\": [\"35444283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MMB-FOXM1/CDK1 axis supported by transcriptional data, not fully reconstituted\", \"biomarkers distinguishing responders incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"FBXW7-CCNE1 turnover was shown to be epigenetically tunable: KDM5B demethylates H3K4me3 at the FBXW7 promoter to repress the ligase and thereby stabilize cyclin E1 protein.\",\n      \"evidence\": \"KDM5B knockdown/overexpression with ChIP for H3K4me3 at FBXW7 and CCNE1 protein/mRNA distinction in Ewing sarcoma\",\n      \"pmids\": [\"35428764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single-lab, single-context demonstration\", \"generality across other tumor types untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining further context-specific dependencies — ARID1A-mutant synthetic lethality, mTOR/HR/checkpoint reliance, and CCNE1-driven WEE1i/ATRi sensitivity at S-phase entry — broadened the actionable vulnerability landscape of CCNE1-overexpressing tumors.\",\n      \"evidence\": \"siRNA synthetic-lethal screening, mTOR-inhibitor treatment with RAD51/ATR rescue, and CCNE1 induction with EdU/γH2AX and PDX validation\",\n      \"pmids\": [\"34070839\", \"35732503\", \"34622231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"overlap and hierarchy among these dependencies not resolved\", \"several are single-lab findings\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Assigning CDK2 a specific role in homologous-recombination repair of collapsed replication forks in CCNE1-amplified cells explained why CDK2 inhibition synergizes with DNA-damaging agents in this context.\",\n      \"evidence\": \"CRISPR whole-genome screens with replication-fork-collapse and HR-repair assays plus combination studies\",\n      \"pmids\": [\"37519629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether this CDK2 function is fully independent of its cyclin E1 G1/S role not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Newer therapeutic strategies — PKMYT1+ATR co-inhibition and a CDK2 PROTAC that co-depletes CDK2 and cyclin E1 — translated the mechanistic dependencies into agents with CCNE1-selective efficacy, including resensitization of palbociclib-adapted cells.\",\n      \"evidence\": \"Pharmacological combination with CDK1-activation/γH2AX readouts in PDX, and a CDK2 PROTAC degrader with RB-phosphorylation and antiproliferative assays\",\n      \"pmids\": [\"40169546\", \"40250405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"clinical durability and resistance mechanisms not established\", \"PROTAC data single-lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that cyclin E1 physically binds ANLN and protects it from FZR1-mediated ubiquitination revealed a CDK2-independent, substrate-stabilizing activity of cyclin E1.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, and site-directed mutagenesis of the ANLN ubiquitination site in TNBC\",\n      \"pmids\": [\"40346052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"structural basis of the CCNE1-ANLN interaction unknown\", \"whether CDK2 contributes to this function untested\", \"single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How cyclin E1 dosage mechanistically couples to centrosome overduplication and replication-stress generation, and which of the many synthetic-lethal dependencies offers the most durable clinical window, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no reconstituted molecular pathway from cyclin E1 to centrosome amplification\", \"relative therapeutic priority among PKMYT1, CDK2, WEE1/ATR, mTOR dependencies undefined\", \"in vivo resistance mechanisms across modalities not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 16]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 11, 16]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 4, 7]}\n    ],\n    \"complexes\": [\"cyclin E1-CDK2 complex\"],\n    \"partners\": [\"CDK2\", \"FBXW7\", \"ANLN\", \"RB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}