CCNE1: A Cell Cycle Regulator That Influences Tumor Progression

Dysregulation of CCNE1 is a recurrent feature of human cancer that operates at multiple levels—from driving tumor initiation and progression, to shaping clinical outcomes, to dictating therapeutic responsiveness. Rather than being a passive marker of proliferation, CCNE1 actively remodels the cellular landscape in ways that confer selective advantages upon incipient and established tumor cells. In this section, we examine three interrelated dimensions of CCNE1's oncological impact: its role in promoting tumorigenesis and genomic instability, its prognostic significance across cancer types, and its contribution to treatment resistance. The causal link between CCNE1 overexpression and tumor development has been established through functional studies across diverse cancer types. In hepatocellular carcinoma (HCC), Aziz et al. [ 18 ] demonstrated that CCNE1 overexpression drives chromosomal instability (CIN), polyploidy, and DNA double‐strand breaks (DSBs). These manifestations of genomic instability arise primarily from premature S‐phase entry forced by excess CCNE1/CDK2 activity, which disrupts replication dynamics and leads to replication errors, aberrant mitotic progression, and perturbed centromere dynamics. Beyond its direct effects on the cell cycle machinery, CCNE1 overexpression triggers widespread transcriptional reprogramming that enhances oxidative phosphorylation, inducing oxidative stress that contributes to oncogene activation, tumor suppressor inactivation, and metabolic dysfunction [ 18 ]. The oncogenic potential of CCNE1 is amplified by upstream transcriptional regulators. In bladder cancer, the homeobox transcription factor MNX1 directly binds the CCNE1 promoter, upregulating its expression and accelerating G1/S transition to drive sustained tumor cell proliferation [ 19 ]. The MNX1–CCNE1 axis illustrates a broader principle: CCNE1 serves as a downstream effector through which diverse oncogenic signals converge to deregulate the cell cycle, and its overexpression is often the final common pathway linking upstream driver mutations to uncontrolled proliferation. While these mechanistic studies have been conducted predominantly at the cellular level and would benefit from validation in larger cohorts using multi‐omics and functional approaches, they collectively establish CCNE1 as a bona fide oncogenic driver rather than a mere correlate of proliferation. CCNE1 overexpression has been consistently associated with adverse clinical outcomes across a broad range of malignancies [ 20 , 21 , 22 ]. In ovarian cancer, the prognostic impact of CCNE1 exhibits notable subtype specificity. In ovarian clear cell carcinoma (OCCC), CCNE1 overexpression was detected in 23.3% of cases arising in the context of endometriosis and was significantly associated with shortened overall survival (OS) [ 20 ]. In primary ovarian carcinomas more broadly, CCNE1 overexpression—observed in up to 62.3% of cases—correlated strongly with reduced survival, early recurrence, and diminished chemotherapy responsiveness [ 22 ]. A striking exception to this pattern has been documented in high‐grade serous ovarian carcinoma (HGSOC), where a study of nearly 200 patients from the OVCAD consortium identified high CCNE1 expression as an independent predictor of favorable, rather than adverse, overall survival [ 23 ]. This paradoxical finding highlights the context‐dependent nature of CCNE1's prognostic significance. Several explanations have been proposed: HGSOC tumors frequently arise in a hypoxic ascitic microenvironment, and slow‐cycling (low‐CCNE1) cells may paradoxically possess superior metastatic capacity; additionally, patients with high CCNE1 expression may represent a subset of serous carcinoma whose biological features more closely resemble those of Type I epithelial ovarian cancer (EOC), defined by individual genetic alterations, rather than the global genomic instability exhibited by Type II EOC patients [ 23 ]; CCNE1 amplification and BRCA mutations are largely mutually exclusive, and univariate analyses may confound the poor prognosis of BRCA‐mutant tumors with CCNE1 status [ 24 ]; and discordance between immunohistochemical detection of CCNE1 protein and FISH‐based assessment of gene amplification—which reaches 30% in some series [ 25 ]—may further complicate prognostic interpretation. Genome‐wide expression profiling has identified five KEGG pathways significantly correlated with CCNE1 expression levels—including activation of cell cycle and viral carcinogenesis pathways and suppression of Fanconi anemia‐related pathways—that may partially underlie these subtype‐dependent effects [ 23 ]. Integrative single‐cell and spatial transcriptomic analysis revealed that in spatial regions with high CCNE1 expression, elevated expression of VEGFB and FBLN2, as well as enrichment of cell adhesion pathways, were observed. These findings further support the role of CCNE1 in promoting structural remodeling and local progression of HGSOC; however, they are associated with invasive tumor behavior and poor prognosis, and do not reveal a relationship with better survival rates [ 26 ]. In another study, the expression of cyclin E detected by immunohistochemical analysis was not significantly correlated with outcomes in patients with advanced serous EOC either. It is considered that the diversity of histological types, different tumor stages, tumor heterogeneity, patient ethnic backgrounds, research methodologies, and sample sizes in EOC may contribute to the inconsistency of results. Therefore, in future studies, we suggest focusing on advanced serous cases (Stage III/IV) from the same source and adopting similar surgical and chemotherapy protocols to eliminate such biases [ 27 ]. In breast cancer, the prognostic power of CCNE1 was compellingly demonstrated by Keyomarsi et al. [ 21 ], who reported that 78% of patients with high CCNE1 expression died within 5 years of diagnosis, compared to only 5% of those with low expression. Notably, CCNE1 outperformed conventional proliferation markers such as Ki‐67 in stratifying patient outcomes. In lung cancer, CCNE1 overexpression promotes tumor growth and metastasis and correlates with significantly worse OS and disease‐specific survival (DSS) in non‐small cell lung cancer (NSCLC), with an even stronger impact on OS in lung squamous cell carcinoma (LUSC) [ 28 , 29 ]. Both the CCNE1 gene and its protein product have been validated as early diagnostic biomarkers in LUAD and LUSC [ 28 , 29 ]. Collectively, these findings establish CCNE1 as a robust, albeit context‐dependent, prognostic indicator that frequently surpasses conventional markers in predictive power. Beyond its roles in tumor initiation and prognostication, CCNE1 dysregulation is a critical determinant of therapeutic response across multiple treatment modalities [ 23 , 24 , 25 , 30 , 31 , 32 ]. The mechanistic basis for this resistance is best understood in the context of CDK4/6 inhibitor therapy. In hormone receptor‐positive (HR+)/HER2‐negative breast cancer, the combination of CDK4/6 inhibitors with endocrine therapy represents the standard of care; however, elevated CCNE1 circumvents CDK4/6 blockade by activating CDK2, which directly phosphorylates Rb and drives G1‐to‐S progression independently of CDK4/6 activity [ 24 , 30 ]. This bypass mechanism results in significantly shortened progression‐free survival (PFS) and underscores the need to assess CCNE1 status when considering CDK4/6 inhibitor therapy. In bladder cancer, CCNE1 expression is markedly upregulated in cisplatin‐resistant tumors, as demonstrated through integrated microarray, quantitative RT‐PCR, and Western blot analyses [ 31 ]. CCNE1 overexpression accelerates cell cycle progression and attenuates chemotherapy‐induced DNA damage responses, thereby mediating cisplatin resistance. Similarly, in breast cancer, CCNE1 overexpression has been linked to resistance against trastuzumab and other HER2‐targeted agents. The interplay between CCNE1 and TP53 is particularly instructive in understanding therapeutic vulnerabilities. CCNE1 overexpression frequently coexists with TP53 dysfunction—a pattern evident in HGSOC [ 23 , 32 ] and gastric cancer [ 33 , 34 ]. When the G1/S checkpoint is compromised by TP53 loss, sustained CCNE1 activity forces cells into S phase under unresolved replication stress, generating stalled forks and accumulated DNA damage [ 35 ]. This creates a state of heightened dependence on the remaining G2/M checkpoint governed by WEE1 kinase. Pharmacological inhibition of WEE1—using agents such as adavosertib—abrogates this compensatory checkpoint, driving tumor cells with high replication stress into mitotic catastrophe [ 35 ]. A multicenter Phase II trial demonstrated that adavosertib exhibits robust clinical activity in refractory solid tumors harboring CCNE1 amplification, validating this synthetic lethal strategy [ 35 ]. In gastric cancer, co‐alteration of CCNE1 and TP53 has been associated with significant liver metastasis, indicating that this combination not only influences therapeutic sensitivity but also promotes invasive and metastatic behavior [ 33 ]. Thus, CCNE1 stands at the intersection of cell cycle dysregulation and therapeutic resistance, and its expression status holds considerable promise for guiding personalized treatment decisions—particularly when integrated with knowledge of co‐occurring genetic alterations and combined with therapies that exploit DNA damage response vulnerabilities.

Liang Yan: writing – original draft. Ning Tang: supervision, resources, funding acquisition, visualization. Yanling Li: conceptualization, supervision. Qian He: data curation, investigation. Chen Long: funding acquisition, supervision. Yanhong Zhou: writing – review and editing, resources, supervision. Siyi Liu: data curation, investigation.

The authors have nothing to report.

This study was supported by the Hunan Provincial Natural Science Foundation (2025JJ50487, 2025JJ80840, and 2025JJ80826); the Health Commission of Hunan Province Research Project (B202304016612); this study was supported by the National Natural Sciences Foundation of China (82273219 and 82571530); the Hunan Cancer Hospital Climb Plan (QH2023004), and the High‐Level Talent Support Program of Hunan Cancer Hospital (20250731‐1024).

Genomic instability is a fundamental hallmark of cancer, manifesting as mutations, chromosomal rearrangements, aneuploidy, and copy number alterations that collectively erode genetic integrity and drive malignant progression [ 36 ]. Among the diverse forms of genomic instability affecting CCNE1 in human cancer, gene amplification is the predominant and most clinically significant aberration [ 8 , 32 , 37 , 38 , 39 , 40 ]. CCNE1 amplification leads to aberrant upregulation of the encoded protein, which in turn drives a cascade of pathological consequences—from accelerated cell cycle progression and replication stress to acquired therapeutic resistance—while simultaneously creating targetable vulnerabilities that can be exploited therapeutically. CCNE1 amplification—defined as an abnormal increase in gene copy number—is consistently observed across aggressive tumor subtypes, with amplification frequencies exceeding 7.5% in HGSOC, LUAD, LUSC, and endometrial carcinomas [ 23 , 29 , 32 ]. Across these cancer types, CCNE1 amplification is strongly associated with reduced overall survival (OS) and progression‐free survival (PFS), as well as with chemoresistance in entities such as desmoplastic melanoma [ 23 , 29 , 32 ]. In endometrial cancer, CCNE1‐amplified tumors exhibit a pronounced dependency on CCNE1‐driven signaling pathways for proliferation and survival [ 13 ], and the antidiabetic agent metformin has shown enhanced antitumor efficacy in CCNE1‐overexpressing HGSOC, potentially through CCNE1/2 downregulation [ 41 ]. Mechanistically, CCNE1‐amplified cancer cells exhibit accelerated G1/S transition kinetics that intensify replication stress at active forks, elevating the frequency of DNA double‐strand breaks (DSBs) [ 32 ]. As a compensatory mechanism, these cells become critically dependent on the S‐phase and G2/M checkpoint kinases ATR (ataxia telangiectasia and Rad3‐related) and WEE1 for survival. WEE1 phosphorylates Tyr15 of CDK1/2 to restrain premature replication initiation and allow time for DNA repair, while ATR activates CHK1 and suppresses CDC25 phosphatases to prevent premature mitotic entry [ 32 , 37 ]. This heightened dependency on ATR‐ and WEE1‐mediated checkpoint control renders CCNE1‐amplified cells exquisitely sensitive to pharmacological inhibition of either kinase. Preclinical studies have demonstrated that tumors with high CCNE1 copy numbers (CN > 5) are particularly responsive to WEE1 inhibitors (WEE1i) and ATR inhibitors (ATRi) [ 32 , 35 , 37 ]. The clinical relevance of this vulnerability was confirmed in a multicenter Phase II trial in which adavosertib—a selective WEE1 inhibitor—produced meaningful antitumor activity in heavily pretreated patients with CCNE1‐amplified solid tumors, while maintaining a manageable safety profile with reduced incidences of anemia, neutropenia, and nausea relative to conventional chemotherapy [ 35 , 42 ]. Meanwhile, four additional ATRi small‐molecule inhibitors are presently being evaluated in Phase I and Phase II clinical trials against a range of gynecological cancers and other solid tumors [ 43 , 44 ]. Furthermore, combined WEE1 and ATR inhibition exerts synergistic antitumor effects in CCNE1‐overexpressing preclinical models, potently inducing replication stress‐associated DNA damage and apoptosis while permitting dose reduction of each agent to mitigate hematologic and other toxicities [ 45 ]. These regulatory relationships are depicted in Figure  3 . Genomic instability caused by CCNE1 gene amplification and the regulatory roles of ATR and WEE1. In CCNE1‐amplified tumors, elevated CCNE1 protein accelerates cell cycle progression, increasing replication fork stress and double‐strand breaks (DSBs). Cells consequently become dependent on WEE1—which phosphorylates CDK1/2 Tyr15 to restrain replication initiation—and ATR—which activates CHK1 and suppresses CDC25 phosphatases to limit mitotic progression—to maintain genome integrity. A defining feature of CCNE1‐amplified tumors is their retention of functional homologous recombination (HR) repair, in marked contrast to BRCA1/2‐mutant cancers that exhibit homologous recombination deficiency (HRD) [ 1 ]. Multiple studies have demonstrated significant mutual exclusivity between CCNE1 amplification and HRD at the molecular level [ 1 , 24 , 46 ]. This exclusivity has direct clinical consequences: CCNE1‐amplified ovarian cancers show negligible response to PARP inhibitors (PARPi), and high‐level CCNE1 amplification has accordingly been proposed as a negative predictive biomarker for PARPi sensitivity [ 24 ]. The mechanistic basis for PARPi resistance lies in CCNE1's ability to sustain HR function: enhanced CDK2 activity accelerates G1/S transition and promotes HR‐dependent repair of stalled replication forks, thereby mitigating the cytotoxic effects of platinum agents and PARP inhibitors [ 38 , 47 ]. However, this dependence on HR also creates therapeutic opportunities. CDK2 has been identified as a non‐redundant regulator of HR repair specifically in the context of CCNE1 amplification [ 48 ], and combined CDK2 inhibition with DNA‐damaging agents can effectively abrogate HR repair and induce synthetic lethality in CCNE1‐amplified cells. Moreover, CHK1 inhibitors such as SRA737 have shown notable antitumor activity in CCNE1‐amplified HGSOC subpopulations by exacerbating replication stress beyond tolerable thresholds [ 47 ]. Further complexity arises from the adaptive responses mounted by CCNE1‐amplified tumors. In HGSOC, mTOR signaling promotes the survival of polyploid giant cancer cells (PGCCs)—a subpopulation with enhanced metastatic potential that depends on functional HR repair [ 48 , 49 ]. mTOR inhibitors (MTORi) can induce a functional HR‐deficient state by downregulating HR pathway and DNA damage checkpoint genes, thereby reducing PGCC formation and resensitizing tumor cells to PARP inhibitors [ 49 ]. This observation supports the clinical exploration of MTORi–PARPi combinations in CCNE1‐amplified, HR‐proficient tumors. Taken together, CCNE1 amplification sculpts a distinctive therapeutic resistance phenotype by sustaining HR functionality while simultaneously creating multiple druggable dependencies. Future precision oncology strategies that stratify patients by CCNE1 copy number and HR status hold considerable promise for overcoming the limitations of conventional therapies. The concept of synthetic lethality—whereby simultaneous perturbation of two genes or pathways results in cell death while alteration of either alone is tolerated—has gained considerable traction in CCNE1‐amplified cancers [ 32 , 39 , 50 , 51 ]. A paradigmatic example is the synthetic lethal relationship between PKMYT1 loss and CCNE1 amplification [ 39 ]. PKMYT1 is a kinase that negatively regulates CDK1 through inhibitory phosphorylation; its loss leads to CDK1 hyperactivation. In the context of CCNE1 amplification, which activates the MYBL2–MuvB (MMB)–FOXM1 complex to drive proliferation, the combined dysregulation of CDK1 generates excessive mitotic activity and catastrophic chromosomal damage, ultimately causing cell death [ 32 , 39 ]. The molecular basis of this interaction is schematically illustrated in Figure  4 . Mechanism of synthetic lethality between PKMYT1 deletion and CCNE1 amplification. PKMYT1 inhibits CDK1 phosphorylation to restrain its activity. PKMYT1 deletion increases CDK1 activity, promoting mitosis via CCND1/CDK1 complexes. Concurrent CCNE1 amplification further accelerates cell division. The combined pressure exceeds checkpoint capacity, generating catastrophic DNA double‐strand breaks (DSBs) and synthetic lethality. Another notable interaction involves CCNE1 amplification and BRCA1 deficiency: although both alterations independently promote genomic instability, they are typically mutually exclusive, and their experimental co‐occurrence leads to synthetic lethality because the intact HR pathway on which CCNE1‐amplified cells depend is disrupted [ 50 ]. In ovarian clear cell carcinoma, ARID1A mutations—which impair chromatin remodeling and G1/S transition control—are highly prevalent and closely associated with CCNE1 amplification; inhibiting CCNE1 in the ARID1A‐mutant context induces cell cycle arrest and tumor regression [ 51 ]. These synthetic lethal relationships suggest that rational combination therapies may achieve both enhanced efficacy and reduced toxicity relative to monotherapy. For instance, combining PKMYT1 inhibitors (PKMYT1i) with ATR inhibitors has shown greater antitumor activity and improved tolerability than either agent alone in CCNE1‐amplified models [ 32 ]. To date, a number of preclinical studies have demonstrated the synergy between PKMYT1 inhibitors and ATR inhibitors using in vitro cell lines and patient‐derived xenograft (PDX) mouse models, encompassing endometrial carcinoma, ovarian cancer, triple‐negative breast cancer, Rb1‐deficient breast cancer, among others [ 52 , 53 , 54 ]. Mechanistically, PKMYT1i induces DNA damage and activates the ATR–CHK1 pathway, while ATRi further suppresses CDC25 phosphatase activity, enhancing CDK1‐pT14 dephosphorylation and driving S‐phase cells into premature, catastrophic mitosis [ 32 ]. Additionally, co‐amplification of CCNE1 with BRD4—a transcriptional co‐regulator that bridges promoters and enhancers—has been documented in HGSOC and is associated with particularly poor overall survival, though the mechanistic interplay between these two amplified genes remains to be elucidated [ 55 ]. Systematic exploration of additional synthetic lethal interactions involving CCNE1 amplification, and their validation in clinically relevant models, remains a high priority for the field. An emerging dimension of CCNE1 biology is its impact on the tumor immune microenvironment (TIME), with implications for immunotherapy efficacy [ 29 , 34 ]. CCNE1 amplification drives chromosomal instability (CIN), which exerts dual, context‐dependent effects on antitumor immunity. On the one hand, chromosome missegregation can generate micronuclei whose rupture releases cytoplasmic DNA, activating the cGAS–STING pathway and downstream Type I interferon (IFN) signaling to stimulate innate and adaptive immune responses [ 34 ]. On the other hand, chronic or extreme CIN—particularly in the context of widespread aneuploidy—can promote immune evasion by disrupting interferon signaling in B cells, neutrophils, and T cells, thereby fostering an immunosuppressive microenvironment that may undermine the efficacy of immune checkpoint inhibitors [ 34 ]. Beyond the indirect effects mediated by CIN, CCNE1 expression levels are directly correlated with patterns of immune infiltration. In LUAD and LUSC, high CCNE1 expression is positively associated with infiltration of CD8+ T cells, CD4+ T cells, macrophages, and natural killer (NK) cells, but negatively correlated with B cell infiltration [ 29 ]. Although the causal mechanisms underlying these associations remain to be elucidated, they suggest that CCNE1 dysregulation may shape the TIME through modulation of chemokine networks, antigen presentation machinery, or immune checkpoint molecule expression. In gastric and gastroesophageal junction adenocarcinomas, CCNE1 amplification‐associated CIN has been proposed to contribute to the lack of survival benefit from trastuzumab in HER2‐positive patients, potentially through CIN‐driven immune remodeling [ 34 ]. Moreover, these findings have been validated in multiple in vivo experiments, including mouse fallopian tube epithelial organoids, mouse HGSC models, and mouse hepatocellular carcinoma models, among others [ 56 , 57 ]. These observations suggest that CCNE1 amplification constructs a complex immune milieu that contains both pro‐inflammatory and immunosuppressive components. Deciphering the specific mechanisms by which CCNE1‐driven CIN alters immune cell function—and determining whether therapies targeting CCNE1‐associated vulnerabilities (CDK2, WEE1, or ATR inhibitors) can be rationally combined with immunotherapy—represents an important frontier for translational research in CCNE1‐amplified cancers. Currently, relevant studies have also been initiated. For example, in a mouse model of GEA (gastroesophageal adenocarcinoma) with CCNE1 amplification, PKMYT1i was found to promote T‐cell infiltration, reduce myeloid cells, and synergize with anti‐PD‐1 therapy to induce tumor regression; additionally, a Phase I clinical trial has demonstrated that the combination of WEE1i and an anti‐PD‐L1 agent exhibits improved safety, tolerability, and preliminary clinical activity [ 58 , 59 ].

The body of evidence reviewed here establishes CCNE1 as a central node in the interface between cell cycle regulation and tumor biology. Its dysregulation—whether through gene amplification, transcriptional activation, or impaired degradation—drives multiple hallmarks of cancer, including sustained proliferation, genomic instability, and therapeutic resistance. At the same time, the vulnerabilities created by CCNE1 overexpression, particularly the dependence on ATR‐, WEE1‐, and CDK2‐mediated checkpoint and repair pathways, provide a compelling rationale for molecularly targeted therapeutic strategies. Nevertheless, several challenges must be addressed before the translational promise of CCNE1‐focused approaches can be fully realized. First, a substantial proportion of current evidence derives from bioinformatics analyses and retrospective studies, which, while hypothesis‐generating, are subject to inherent biases and require prospective validation. Second, many functional studies have been conducted in a limited number of cell line models that capture only a narrow spectrum of the genetic contexts in which CCNE1 is dysregulated; the tumor type‐specific and genetic context‐dependent effects of CCNE1—exemplified by the divergent prognostic implications in HGSOC versus other ovarian cancer subtypes—underscore the need for systematic investigation across diverse tumor backgrounds. Third, biomarker‐driven clinical studies targeting CCNE1‐amplified tumors have been constrained by small sample sizes, reflecting the practical challenges of recruiting molecularly defined patient populations, and many studies have reported correlations between CCNE1 status and clinical parameters without elucidating the underlying mechanistic basis. Fourth, the interconnected nature of CCNE1 regulatory networks—spanning transcriptional control, non‐coding RNA modulation, epigenetic regulation, and post‐translational modification—presents both an opportunity and a challenge: while the multiplicity of regulatory nodes offers many potential therapeutic targets, the redundancy and cross‐talk within these networks may limit the efficacy of single‐agent interventions. Looking forward, several priorities emerge. Mechanistic studies employing multi‐omics approaches—integrating genomics, transcriptomics, proteomics, and phosphoproteomics—in well‐characterized clinical cohorts are needed to define the specific pathways through which CCNE1 promotes tumor progression in distinct genetic contexts. For example, for the specific subtype of high‐grade serous ovarian cancer (HGSOC) that accounts for approximately 20% of cases with CCNE1 amplification and is mutually exclusive with BRCA1/2 mutations, future research should be structured around a prospective multicenter cohort (target enrollment: 300 cases). Uniform molecular stratification should be performed using FISH and BRCA1/2 testing, dividing patients into four groups: CCNE1amp/BRCAwt, CCNE1amp/BRCAmut, CCNE1non‐amp/BRCAmut, and double‐negative. Integrated whole‐exome sequencing, transcriptomics, and phosphoproteomics should be employed to systematically dissect the specific molecular characteristics of this subtype, focusing on the CDK2 substrate phosphorylation network, replication stress signaling (ATR/CHK1 pathway), and E2F transcriptional programs. Concurrently, a patient‐derived organoid (PDO) biobank from CCNE1amp/BRCAwt patients should be established as a platform to screen for optimal single‐agent and platinum‐based combination regimens of CDK2 inhibitors (e.g., BLU‐222 and PF‐07104091), a WEE1 inhibitor (adavosertib), and an ATR inhibitor (ceralasertib). Combined with single‐cell RNA sequencing to reveal intratumoral heterogeneity and the evolution of drug‐resistant clones, the PDO drug‐sensitivity data should ultimately be correlated with first‐line progression‐free survival (PFS) to establish a predictive biomarker system that can guide stratified clinical treatment. Besides the development and validation of standardized, clinically deployable assays for CCNE1 amplification and overexpression (harmonizing IHC and FISH methodologies) will be essential for accurate patient stratification. Rational combination strategies—pairing inhibitors of CCNE1‐associated vulnerabilities (CDK2, WEE1, and ATR) with immunotherapy, PARP inhibitors, or conventional chemotherapy—should be explored in biomarker‐selected patient populations. The non‐coding RNA regulatory network and the epigenetic machinery governing CCNE1 expression warrant further investigation as sources of novel therapeutic targets and diagnostic biomarkers. In conclusion, CCNE1 stands as a paradigm for how aberrant cell cycle control drives tumorigenesis while simultaneously exposing targetable liabilities. The convergence of mechanistic insights, preclinical validation, and early clinical data provides a strong foundation for the development of CCNE1‐directed precision oncology. With sustained interdisciplinary effort—bridging basic discovery, translational research, and clinical investigation—the therapeutic potential of targeting CCNE1 in cancer may ultimately be realized, offering new hope for patients with CCNE1‐driven malignancies.

The periodic expression of CCNE1 is orchestrated through a multilayered regulatory system that integrates transcriptional control, post‐transcriptional modulation, and targeted proteolysis. At the transcriptional level, the E2F family of transcription factors serves as the principal driver of CCNE1 expression. During G1 phase, E2F is sequestered by the retinoblastoma protein (Rb). Mitogenic signals—mediated through pathways such as Ras/MAPK and c‐MYC—induce the expression of cyclin D, which partners with CDK4/6 to phosphorylate and inactivate Rb [ 9 , 10 , 11 ]. This phosphorylation releases E2F, enabling it to transactivate CCNE1 and other genes required for S‐phase entry. The newly synthesized CCNE1 protein then binds CDK2, and the resulting CCNE1/CDK2 complex further phosphorylates Rb in a positive‐feedback loop that reinforces E2F release and drives the G1/S transition [ 9 , 12 ]. Post‐transcriptional regulation adds an additional layer of control. MicroRNAs, including miR‐17‐5p and miR‐34a, target the 3′‐untranslated region (3′‐UTR) of CCNE1 mRNA to suppress its translation; their downregulation in certain tumors contributes to CCNE1 overexpression. Equally critical is the timely degradation of CCNE1 protein, which is mediated primarily by the SCF^FBXW7 ubiquitin ligase complex. Following phosphorylation at residues including Thr62 and Ser372, CCNE1 is recognized by the F‐box protein FBXW7, polyubiquitinated, and targeted to the proteasome for destruction [ 13 ]. This degradation initiates early in S phase, ensuring that CDK2 activity is extinguished once DNA replication has commenced. As a result, CCNE1 protein levels progressively accumulate during G1, peak at the G1/S boundary, and decline through S and G2 phases [ 14 ]. The expression of CCNE1 and its principal degradation pathway are summarized in Figure  1 . Expression of the CCNE1 gene and degradation of the CCNE1 protein. Under mitogenic stimulation, E2F is released from Rb‐mediated repression and drives CCND transcription, initiating the cyclin D–CDK4/6–Rb–E2F positive‐feedback loop. Released E2F subsequently activates CCNE1 transcription. The CCNE1 protein is recognized by the SCF^FBXW7 complex, ubiquitinated, and targeted to the proteasome for degradation. The CCNE1 protein exerts its biological functions through two distinct modalities, as illustrated in Figure  2 . The canonical CDK2‐dependent mechanism involves the formation of the CCNE1/CDK2 holoenzyme, which requires phosphorylation of CDK2 at its T‐loop region [ 15 ]. Once activated, the complex mediates the peak activity of histone acetyltransferases such as p300/CBP at the G1/S transition, promoting chromatin relaxation and facilitating DNA replication [ 16 ]. The complex also helps maintain appropriate centrosome numbers during mitotic progression [ 1 ]. Mechanism of CCNE1 protein in regulating the G1/S phase transition. The CCNE1 protein regulates G1/S progression via two principal mechanisms. First, the CCNE1/CDK2 complex activates p300/CBP, driving histone acetyltransferase (HAT) activity that relaxes chromatin for DNA unwinding and replication, while also maintaining normal centrosome numbers. Second, CCNE1 functions independently of CDK2 by participating in the assembly of minichromosome maintenance (MCM) complexes, promoting the formation of functional DNA replication initiation complexes. Beyond its CDK2‐dependent roles, CCNE1 possesses CDK2‐independent functions that directly contribute to replication control. CCNE1 binds DNA near replication origins and physically interacts with components of the pre‐replication complex, including the licensing factor Cdt1 and the origin recognition complex (ORC) [ 17 ]. Additionally, a 20‐amino‐acid centrosome localization sequence (CLS) within CCNE1 directs the protein to centrosomes, where it promotes centrosome duplication [ 17 ]. CCNE1 has also been implicated in cell migration, DNA repair, anti‐apoptotic signaling, endocytosis, and transcriptional regulation, suggesting a broader functional repertoire than initially appreciated. When CCNE1 expression escapes its normal periodic control—whether through gene amplification, transcriptional dysregulation, or impaired degradation—the consequences for genome integrity are profound. Elevated CCNE1 levels accelerate G1/S progression, forcing cells into S phase before replication origins are adequately licensed, which generates replication stress, stalled forks, and DNA double‐strand breaks [ 1 ]. These insults drive chromosomal instability and increase the mutation rate of genes governing proliferation and survival, establishing a permissive environment for malignant transformation. Thus, the precise temporal control of CCNE1 expression and degradation is not merely a feature of normal cell cycle progression—it is an essential safeguard against tumorigenesis.

The expression and activity of CCNE1 are governed by a multilayered regulatory architecture that extends well beyond the core E2F–Rb transcriptional axis. Non‐coding RNAs, epigenetic modifications, and post‐translational mechanisms collectively fine‐tune CCNE1 levels, and perturbations at any of these regulatory tiers can contribute to its dysregulation in cancer. Understanding these networks is essential not only for a complete picture of CCNE1 biology but also for identifying therapeutic entry points upstream of CCNE1 itself. Non‐coding RNAs—including microRNAs (miRNAs), circular RNAs (circRNAs), and long non‐coding RNAs (lncRNAs)—constitute a major regulatory interface controlling CCNE1 expression, primarily through post‐transcriptional mechanisms that modulate mRNA stability and translation efficiency [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ]. These regulatory relationships are summarized in Figure  5 . Regulatory mechanism of microRNA and lncRNA on CCNE1 gene expression. Most miRNAs directly inhibit CCNE1 expression by binding to its 3′‐UTR, thereby suppressing the oncogenic consequences of elevated CCNE1 protein (enhanced proliferation, EMT, etc.). lncRNAs and circRNAs commonly function as ceRNAs, competitively binding miRNAs to relieve their suppression of CCNE1, ultimately increasing CCNE1 protein levels and promoting tumor progression. MicroRNAs typically suppress CCNE1 expression through direct base‐pairing between their seed region and the 3′‐UTR of CCNE1 mRNA [ 61 ]. Tumor‐suppressive miRNAs that negatively regulate CCNE1 have been identified across diverse cancer types. In cholangiocarcinoma, miR‐874 suppresses CCNE1, thereby inhibiting NF‐κB signaling and epithelial‐mesenchymal transition (EMT) [ 64 ]. In acute promyelocytic leukemia (APL), miR‐15b promotes differentiation and inhibits proliferation through CCNE1 downregulation [ 71 ]. In epithelial ovarian cancer (EOC), miR‐424‐5p—normally a CCNE1 repressor—is itself downregulated, leading to CCNE1 derepression and poor prognosis [ 63 ]. In glioma, reduced expression of miR‐497 or its host gene MIR497HG releases CCNE1 from negative regulation, promoting proliferation; conversely, their overexpression suppresses glioma growth through coordinated downregulation of CCNE1 and the miR‐588/TUSC1 axis [ 62 ]. In hepatocellular carcinoma, miR‐7 directly targets the CCNE1 3′‐UTR to suppress tumor progression [ 72 ]. While most miRNAs repress CCNE1, exceptions exist: miR‐16‐1 has been reported to enhance CCNE1 expression in cervical cancer cells through an as‐yet‐uncharacterized mechanism [ 76 ]. Indirect miRNA‐mediated regulation has also been documented, as exemplified by miR‐141 in lung adenocarcinoma, which targets HOXC13 to indirectly modulate CCNE1 levels and G1‐phase progression [ 69 ]. Circular RNAs (circRNAs) regulate CCNE1 through diverse mechanisms that extend beyond the canonical miRNA sponge paradigm [ 65 , 66 , 70 , 74 ]. In melanoma, CircROR1 recruits the histone acetyltransferase KAT2A to the CCNE1 promoter, enhancing H3K9 acetylation (H3K9ac) and directly driving CCNE1 transcription [ 66 ]. In colorectal cancer (CRC), CircSEMA5A functions as a competing endogenous RNA (ceRNA) for miR‐195‐5p, sequestering this miRNA to derepress CCNE1 expression [ 70 ]. Similar ceRNA mechanisms operate in NSCLC, where CircDENND2A sponges miR‐34a [ 74 ] and hsa_circ_0062389 sponges miR‐103a‐3p [ 65 ], both resulting in CCNE1 upregulation and enhanced tumor aggressiveness. Long non‐coding RNAs (lncRNAs) add further regulatory complexity, predominantly functioning as ceRNAs [ 36 , 60 , 67 , 73 ]. In LUAD, RAET1K sponges miR‐135a‐5p to derepress CCNE1 [ 60 ]; in small cell lung cancer, LINC00355 sponges miR‐195 to stimulate proliferation and inhibit apoptosis via CCNE1 [ 67 ]; and in triple‐negative breast cancer (TNBC), SENP3‐EIF4A1 sponges miR‐195‐5p to drive CCNE1‐mediated malignant phenotypes [ 60 ]. In cervical cancer, LNC_000231 sponges miR‐497‐5p to maintain elevated CCNE1 levels [ 73 ]. The clinical significance of lncRNA‐mediated CCNE1 regulation is underscored by its role in chemoresistance: in small cell lung cancer, exosomal lncRNA MEG3 derived from cancer‐associated fibroblasts sponges miR‐15a‐5p to derepress CCNE1, thereby promoting cisplatin resistance [ 67 ]. Beyond the ceRNA mechanism, antisense lncRNAs can regulate CCNE1 through transcriptional co‐factor recruitment [ 6 , 68 , 75 ]. In pediatric Wilms tumor, Mylk antisense RNA 1 (Mylk‐AS1) recruits the transcription factor TCF7L2 to the CCNE1 locus, positively driving its expression [ 75 ]. In CRC, MCF2L antisense RNA 1 (MCF2L‐AS1) functions as a ceRNA for miR‐874‐3p, derepressing CCNE1 to enhance invasiveness [ 6 ]. In NSCLC, LUAD, and prostate cancer, OXCT1‐AS1 inhibits miR‐195 to derepress CCNE1, promoting proliferation and metastasis [ 68 ]. The components of this network represent potential diagnostic biomarkers and therapeutic targets within the non‐coding RNA–CCNE1 axis. Beyond non‐coding RNAs, CCNE1 expression and protein stability are subject to regulation by DNA methylation, histone modifications, RNA modifications, and post‐translational modifications including ubiquitination and SUMOylation [ 77 , 78 , 79 , 80 , 81 ]. At the DNA level, the CCNE1 promoter exhibits significant hypomethylation in uterine corpus endometrial carcinoma (UCEC), suggesting that epigenetic derepression is one route to CCNE1 overexpression [ 80 ]. At the RNA level, CCNE1 mRNA harbors six potential N 6 ‐methyladenosine (m 6 A) modification sites [ 80 ]; in CRC, the m 6 A methyltransferase METTL3 deposits m 6 A marks on CCNE1 mRNA, stabilizing the transcript and upregulating protein expression to drive proliferation [ 81 ]. Histone modifications further diversify the regulatory landscape. In CRC, Aurora kinase B (AurkB) phosphorylates histone H3 at serine 10 (H3S10ph) at the CCNE1 locus, activating transcription and promoting tumor proliferation, invasion, and metastasis [ 78 ]. In Ewing sarcoma, the lysine demethylase KDM5B removes H3K4 trimethylation (H3K4me3) marks from the FBXW7 promoter, suppressing transcription of this E3 ligase. Because FBXW7 mediates CCNE1 ubiquitination and degradation, its KDM5B‐dependent silencing stabilizes CCNE1 protein and drives tumor progression [ 77 ]. Post‐translational mechanisms governing CCNE1 stability are equally important. In Wilms tumor, the deSUMOylase SENP1 stabilizes HIF‐1α, which in turn activates downstream targets including STC1 to upregulate CCNE1—a pathway whose activation correlates with significantly reduced overall and disease‐free survival [ 7 , 79 ]. In hepatocellular carcinoma, SCUBE3 binds TGF‐β receptor II (TGFβRII) to activate TGF‐β signaling, leading to AKT phosphorylation and subsequent inhibition of GSK3β. Since GSK3β promotes the phosphorylation of CCNE1 that is required for FBXW7‐mediated degradation, GSK3β inhibition results in CCNE1 stabilization, driving cell cycle progression and tumor growth [ 79 ]. In aggregate, CCNE1 is governed by a concerted regulatory system spanning transcription, post‐transcription, translation, and post‐translational modification. This multi‐tiered architecture provides numerous potential intervention points, and a deeper understanding of how these regulatory layers interact—and which are most amenable to therapeutic manipulation—is an ongoing priority. As the CCNE1 regulatory network has expanded, several upstream factors—including KDM5B, SENP1, and SCUBE3—have been identified as potential therapeutic targets whose inhibition could indirectly reduce CCNE1 levels, thereby restoring cell cycle control and treatment sensitivity [ 7 , 77 , 79 ]. The splicing inhibitor spliceostatin A (SSA) provides a proof of concept for this strategy: SSA suppresses CCNE1 through a dual mechanism involving (i) upregulation of CDKN1B and its C‐terminally truncated form p27, which binds and inhibits the Cyclin E–CDK2 complex to arrest cells at G1; and (ii) reduced splicing fidelity at exon junctions in CCNE1 and E2F1 pre‐mRNAs, generating aberrant transcripts and diminished protein expression that synergistically impair G1/S and G2/M transitions [ 82 ]. Despite their theoretical appeal, upstream targeting strategies face substantial translational hurdles. First, splicing regulation is inherently global—broad‐spectrum agents such as SSA may perturb normal splicing of numerous genes, generating significant off‐target effects and cellular toxicity [ 82 ]. Second, all evidence for SSA‐mediated CCNE1 regulation derives from cell line studies, without validation in patient‐derived organoids (PDOs) or in vivo models, and no Phase I clinical data exist [ 82 ]. Third, selective small‐molecule inhibitors of KDM5B, SENP1, or SCUBE3 with drug‐like pharmacological properties have yet to be reported [ 7 , 77 , 79 ]. Future development efforts should prioritize selective modulators—including PROTAC degraders, allosteric inhibitors, and tissue‐specific delivery platforms—and their rigorous validation in clinically predictive models, to advance these strategies from experimental observation to therapeutic application. Notably, although no clinically available selective drugs are yet available for these targets, medicinal chemistry efforts have made noteworthy progress. For KDM5B, the pyrazolo[3,4‐b]pyridine‐based KDM5B‐IN4 (IC 50  = 25 nM) has demonstrated in vivo efficacy in mouse xenograft models, while the PROTAC degrader YTHu78, developed from the GSK467 scaffold, achieves a strategic shift from catalytic inhibition to targeted degradation and exhibits antiproliferative activity in hematological tumor cells that is not seen with the parent inhibitor [ 83 , 84 , 85 ]. For SENP1, lead compounds are primarily derived from natural products, among which ursolic acid (IC 50  = 6.4 nM) and its semi‐synthetic derivative Senp1‐IN‐3 represent the current best potency and selectivity and have been functionally positioned as tumor radiosensitizers [ 86 ]. Direct small‐molecule inhibitors of SCUBE3 are still lacking, but the first‐in‐class neutralizing monoclonal antibody reported in 2026 has shown pan‐cancer therapeutic potential in patient‐derived xenograft models of breast and ovarian cancer, suggesting that antibody engineering may be a more feasible intervention avenue for this target at present [ 87 , 88 ]. Regarding the toxicity issues of SSA splicing inhibitors, three parallel strategies provide a developable resolution framework: the PROTAC degradation strategy—exemplified by PROTAC‐O4I2, which degrades SF3B1 via CRBN‐mediated ubiquitination, exhibiting approximately 44‐fold higher antiproliferative activity than the parent inhibitor O4I2, and its catalytic mechanism reduces dependence on sustained target occupancy [ 89 ]; ADC‐based tissue‐specific delivery—Eisai's patented splicing modulator–ADC platform, approved in 2024, conjugates pladienolide‐class payloads with antibodies targeting HER2, CD138, and EPHA2, while Peak Bio's Thailanstatin‐ADC platform (PH‐1) further introduces a dual mechanism with immune memory activation; rational combination therapy based on synthetic lethality—although the Phase I trial of H3B‐8800 did not meet the objective response endpoint [ 90 ], its mechanistic studies revealed that splicing modulators induce aberrant splicing of BRCA1/BRCA2/CHEK2, leading to homologous recombination repair deficiency, which provides a clear preclinical rationale for synthetic lethal combination with PARP inhibitors (validated in STAG2‐mutant AML models), while aberrant transcripts of TMEM14C and RAD51 focus formation can serve as predictive biomarkers to guide patient selection. In summary, the common core of the above strategies lies in replacing broad‐spectrum splicing inhibition with selective mechanisms (PROTAC degradation, ADC‐targeted delivery, synthetic lethality), thereby overcoming the toxicity bottleneck while preserving the therapeutic value of the target.

The authors have nothing to report.

The discovery of cyclins in 1983 as proteins that rapidly accumulate and are degraded in dividing sea urchin embryos [ 1 ] laid the foundation for understanding eukaryotic cell cycle control. By 1991, all five major human cyclin families—CCNA, CCNB, CCNC, CCND, and CCNE—had been isolated through functional complementation in Saccharomyces cerevisiae [ 2 ]. Among these, Cyclin E1 (CCNE1) has emerged as a central regulator of the G1/S phase transition, a critical checkpoint whose dysregulation is a hallmark of human cancer. Encoded by the CCNE1 gene located on chromosome 19q12, CCNE1 consists of four exons and three introns, producing a 2.2 kb mRNA [ 3 ] that is translated into a 50 kDa protein [ 1 ]. The protein contains a highly conserved 87‐amino‐acid cyclin box in its central region, which mediates binding to CDK2 [ 4 ] and is essential for its function. Upon binding CDK2, CCNE1 forms an active kinase complex that phosphorylates downstream targets to promote DNA replication initiation and S‐phase entry [ 5 ]. The abundance and activity of CCNE1 oscillate in a tightly regulated manner: expression peaks at the G1/S boundary and declines rapidly thereafter through ubiquitin‐mediated proteolysis, ensuring orderly cell cycle progression and genome integrity. Aberrant activation of the CCNE1/CDK2 axis—most commonly through CCNE1 gene amplification or overexpression—has been documented across numerous cancer types, including breast, ovarian, gastric, and non‐small cell lung cancers [ 1 , 6 , 7 , 8 ]. Elevated CCNE1 levels drive uncontrolled proliferation, compromise DNA damage repair, and foster genomic instability, all of which contribute to tumor aggressiveness and poor clinical outcomes. Furthermore, CCNE1 dysregulation has been causally linked to resistance against conventional chemotherapy, targeted therapy, and endocrine therapy, positioning it as a key mediator of treatment failure. Given its multifaceted roles in oncogenesis and therapeutic resistance, CCNE1 has attracted considerable attention as both a potential biomarker for risk stratification and a therapeutic target. Strategies under investigation include CDK2‐selective inhibitors, WEE1, and ATR inhibitors that exploit replication stress vulnerabilities in CCNE1‐amplified tumors, and approaches targeting upstream regulatory networks including non‐coding RNAs and epigenetic modifiers. In this review, we present an integrated synthesis of current knowledge on CCNE1—from its fundamental role in cell cycle control through its diverse contributions to tumor biology and treatment resistance—and critically assess the prospects for translating these insights into clinical applications.

The authors declare no conflicts of interest.