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Trends in Cell Biology Sep 2021E-type cyclins, collectively called cyclin E, represent key components of the core cell cycle machinery. In mammalian cells, two E-type cyclins, E1 and E2, activate... (Review)
Review
E-type cyclins, collectively called cyclin E, represent key components of the core cell cycle machinery. In mammalian cells, two E-type cyclins, E1 and E2, activate cyclin-dependent kinase 2 (CDK2) and drive cell cycle progression by phosphorylating several cellular proteins. Abnormally elevated activity of cyclin E-CDK2 has been documented in many human tumor types. Moreover, cyclin E overexpression mediates resistance of tumor cells to various therapeutic agents. Recent work has revealed that the role of cyclin E extends well beyond cell proliferation and tumorigenesis, and it may regulate a diverse array of physiological and pathological processes. In this review, we discuss these various cyclin E functions and the potential for therapeutic targeting of cyclin E and cyclin E-CDK2 kinase.
Topics: Animals; Cell Cycle; Cell Proliferation; Cyclin E; Cyclins; Humans
PubMed: 34052101
DOI: 10.1016/j.tcb.2021.05.001 -
Cell Feb 2023Whole-genome duplication (WGD) is a frequent event in cancer evolution and an important driver of aneuploidy. The role of the p53 tumor suppressor in WGD has been...
Whole-genome duplication (WGD) is a frequent event in cancer evolution and an important driver of aneuploidy. The role of the p53 tumor suppressor in WGD has been enigmatic: p53 can block the proliferation of tetraploid cells, acting as a barrier to WGD, but can also promote mitotic bypass, a key step in WGD via endoreduplication. In wild-type (WT) p53 tumors, WGD is frequently associated with activation of the E2F pathway, especially amplification of CCNE1, encoding cyclin E1. Here, we show that elevated cyclin E1 expression causes replicative stress, which activates ATR- and Chk1-dependent G2 phase arrest. p53, via its downstream target p21, together with Wee1, then inhibits mitotic cyclin-dependent kinase activity sufficiently to activate APC/C and promote mitotic bypass. Cyclin E expression suppresses p53-dependent senescence after mitotic bypass, allowing cells to complete endoreduplication. Our results indicate that p53 can contribute to cancer evolution through the promotion of WGD.
Topics: Humans; Cell Line, Tumor; Cyclin E; Cyclin-Dependent Kinase Inhibitor p21; Gene Duplication; Mitosis; Neoplasms; Tumor Suppressor Protein p53
PubMed: 36681079
DOI: 10.1016/j.cell.2022.12.036 -
Cancer Cell Jun 2021Abnormal activity of the core cell-cycle machinery is seen in essentially all tumor types and represents a driving force of tumorigenesis. Recent studies revealed that... (Review)
Review
Abnormal activity of the core cell-cycle machinery is seen in essentially all tumor types and represents a driving force of tumorigenesis. Recent studies revealed that cell-cycle proteins regulate a wide range of cellular functions, in addition to promoting cell division. With the clinical success of CDK4/6 inhibitors, it is becoming increasingly clear that targeting individual cell-cycle components may represent an effective anti-cancer strategy. Here, we discuss the potential of inhibiting different cell-cycle proteins for cancer therapy.
Topics: Animals; Antineoplastic Agents; Cell Cycle; Cyclin D; Cyclin E; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Humans; Mice; Molecular Targeted Therapy; Neoplasms
PubMed: 33891890
DOI: 10.1016/j.ccell.2021.03.010 -
Clinical Cancer Research : An Official... Nov 2023Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy.
PURPOSE
Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy.
EXPERIMENTAL DESIGN
Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC. In vitro, CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to combinatorial therapy with various treatment regimens, followed by tumor growth assessment. Pharmacodynamic markers in PDXs were characterized by IHC and reverse-phase protein array.
RESULTS
Among several ERBB2-amplified cancers, CCNE1 co-amplification was identified (gastric 37%, endometroid 43%, and ovarian serous adenocarcinoma 41%). We hypothesized that adavosertib may enhance activity of HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd). In vitro, sensitivity to T-DXd was decreased by cyclin E overexpression and increased by knockdown, and adavosertib was synergistic with topoisomerase I inhibitor DXd. In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX models and prolonged event-free survival (EFS) in a HER2-overexpressing gastroesophageal cancer model. T-DXd + adavosertib treatment also increased EFS in other HER2-expressing tumor types, including a T-DXd-treated colon cancer model.
CONCLUSIONS
We provide rationale for combining T-DXd with adavosertib in HER2-expressing cancers, especially with co-occuring CCNE1 amplifications. See related commentary by Rolfo et al., p. 4317.
Topics: Humans; Animals; Mice; Cyclin E; In Situ Hybridization, Fluorescence; Trastuzumab; Receptor, ErbB-2; Camptothecin; Immunoconjugates; Neoplasms
PubMed: 37279095
DOI: 10.1158/1078-0432.CCR-23-0103 -
Journal of Clinical Oncology : Official... May 2019A large-panel gene expression analysis was conducted to identify biomarkers associated with the effectiveness of adding palbociclib to fulvestrant. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
A large-panel gene expression analysis was conducted to identify biomarkers associated with the effectiveness of adding palbociclib to fulvestrant.
METHODS
The PALOMA-3 ( ClinicalTrials.gov identifier: NCT01942135) trial randomly assigned 521 endocrine-pretreated patients with metastatic breast cancer to receive palbociclib plus fulvestrant or placebo plus fulvestrant. Primary analysis was first conducted on 10 genes on the basis of pathway biology and evidence from previous studies followed by a systematic panel-wide search among 2,534 cancer-related genes. The association of gene expression with the effect of palbociclib on progression-free survival (PFS) was evaluated using Cox proportional hazards regression analysis, with gene expression as a continuous variable or dichotomized by median. An independent breast cancer cohort from the Preoperative Palbociclib (POP) Clinical Trial ( ClinicalTrials.gov identifier: NCT02008734) was used for validation, in 61 patients with primary breast cancer treated with 2 weeks of palbociclib.
RESULTS
In the PALOMA-3 trial, 302 patients had tumor tissue analyzed (palbociclib arm, 194 patients; placebo arm, 108 patients). Palbociclib efficacy was lower in patients with high versus low cyclin E1 () mRNA expression (median PFS: palbociclib arm, 7.6 14.1 months; placebo arm, 4.0 4.8 months, respectively; interaction unadjusted = .00238; false discovery rate-adjusted = .0238). mRNA was more predictive in metastatic than in archival primary biopsy tissue samples. No significant interaction was found between treatment and expression levels of CDK4, CDK6, cyclin D1, and RB1. Palbociclib was efficacious in both luminal A and luminal B tumors. High mRNA expression was associated with poor antiproliferative activity of palbociclib in the POP trial ( = .005).
CONCLUSION
Addition of palbociclib to fulvestrant demonstrated efficacy in all biomarker groups, although high mRNA expression was associated with relative resistance to palbociclib.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Cyclin E; Female; Fulvestrant; Gene Expression Profiling; Humans; Neoplasm Metastasis; Oncogene Proteins; Piperazines; Progression-Free Survival; Proportional Hazards Models; Pyridines; RNA, Messenger; Receptors, Estrogen; Receptors, Progesterone
PubMed: 30807234
DOI: 10.1200/JCO.18.00925 -
Molecular Cell Oct 2023Fanconi anemia (FA) signaling, a key genomic maintenance pathway, is activated in response to replication stress. Here, we report that phosphorylation of the pivotal...
Fanconi anemia (FA) signaling, a key genomic maintenance pathway, is activated in response to replication stress. Here, we report that phosphorylation of the pivotal pathway protein FANCD2 by CHK1 triggers its FBXL12-dependent proteasomal degradation, facilitating FANCD2 clearance at stalled replication forks. This promotes efficient DNA replication under conditions of CYCLIN E- and drug-induced replication stress. Reconstituting FANCD2-deficient fibroblasts with phosphodegron mutants failed to re-establish fork progression. In the absence of FBXL12, FANCD2 becomes trapped on chromatin, leading to replication stress and excessive DNA damage. In human cancers, FBXL12, CYCLIN E, and FA signaling are positively correlated, and FBXL12 upregulation is linked to reduced survival in patients with high CYCLIN E-expressing breast tumors. Finally, depletion of FBXL12 exacerbated oncogene-induced replication stress and sensitized cancer cells to drug-induced replication stress by WEE1 inhibition. Collectively, our results indicate that FBXL12 constitutes a vulnerability and a potential therapeutic target in CYCLIN E-overexpressing cancers.
Topics: Humans; Cell Survival; Chromatin; Cyclin E; DNA Damage; DNA Repair; DNA Replication; Fanconi Anemia; Fanconi Anemia Complementation Group D2 Protein; Neoplasms
PubMed: 37591242
DOI: 10.1016/j.molcel.2023.07.026 -
Oncogene Dec 2022Low-molecular-weight cyclin E (LMW-E) is an N-terminus deleted (40 amino acid) form of cyclin E detected in breast cancer, but not in normal cells or tissues. LMW-E...
Low-molecular-weight cyclin E (LMW-E) is an N-terminus deleted (40 amino acid) form of cyclin E detected in breast cancer, but not in normal cells or tissues. LMW-E overexpression predicts poor survival in breast cancer patients independent of tumor proliferation rate, but the oncogenic mechanism of LMW-E and its unique function(s) independent of full-length cyclin E (FL-cycE) remain unclear. In the current study, we found LMW-E was associated with genomic instability in early-stage breast tumors (n = 725) and promoted genomic instability in human mammary epithelial cells (hMECs). Mechanistically, FL-cycE overexpression inhibited the proliferation of hMECs by replication stress and DNA damage accumulation, but LMW-E facilitated replication stress tolerance by upregulating DNA replication and damage repair. Specifically, LMW-E interacted with chromatin and upregulated the loading of minichromosome maintenance complex proteins (MCMs) in a CDC6 dependent manner and promoted DNA repair in a RAD51- and C17orf53-dependent manner. Targeting the ATR-CHK1-RAD51 pathway with ATR inhibitor (ceralasertib), CHK1 inhibitor (rabusertib), or RAD51 inhibitor (B02) significantly decreased the viability of LMW-E-overexpressing hMECs and breast cancer cells. Collectively, our findings delineate a novel role for LMW-E in tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E-overexpressing breast cancers.
Topics: Humans; Female; Cyclin E; Breast Neoplasms; Cyclin-Dependent Kinase 2; Biomarkers, Tumor; Genomic Instability; Protein Kinase Inhibitors; DNA Replication; DNA Damage; DNA Repair
PubMed: 36344674
DOI: 10.1038/s41388-022-02527-z -
Cold Spring Harbor Perspectives in... Jan 2013Developmentally programmed polyploidy occurs by at least four different mechanisms, two of which (endoreduplication and endomitosis) involve switching from mitotic cell... (Review)
Review
Developmentally programmed polyploidy occurs by at least four different mechanisms, two of which (endoreduplication and endomitosis) involve switching from mitotic cell cycles to endocycles by the selective loss of mitotic cyclin-dependent kinase (CDK) activity and bypassing many of the processes of mitosis. Here we review the mechanisms of endoreplication, focusing on recent results from Drosophila and mice.
Topics: Animals; Cell Cycle; Cyclin E; Cyclin-Dependent Kinase 2; DNA Replication; Drosophila; Endoreduplication; Mice; Polyploidy
PubMed: 23284048
DOI: 10.1101/cshperspect.a012948 -
Life Science Alliance May 2022Cyclin E/CDK2 drives cell cycle progression from G1 to S phase. Despite the toxicity of cyclin E overproduction in mammalian cells, the cyclin E gene is overexpressed in...
Cyclin E/CDK2 drives cell cycle progression from G1 to S phase. Despite the toxicity of cyclin E overproduction in mammalian cells, the cyclin E gene is overexpressed in some cancers. To further understand how cells can tolerate high cyclin E, we characterized non-transformed epithelial cells subjected to chronic cyclin E overproduction. Cells overproducing cyclin E, but not cyclins D or A, briefly experienced truncated G1 phases followed by a transient period of DNA replication origin underlicensing, replication stress, and impaired proliferation. Individual cells displayed substantial intercellular heterogeneity in cell cycle dynamics and CDK activity. Each phenotype improved rapidly despite high cyclin E-associated activity. Transcriptome analysis revealed adapted cells down-regulated a cohort of G1-regulated genes. Withdrawing cyclin E from adapted cells only partially reversed underlicensing indicating that adaptation is at least partly non-genetic. This study provides evidence that mammalian cyclin E/CDK inhibits origin licensing indirectly through premature S phase onset and provides mechanistic insight into the relationship between CDKs and licensing. It serves as an example of oncogene adaptation that may recapitulate molecular changes during tumorigenesis.
Topics: Animals; Cell Cycle; Cell Division; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; Cyclins; DNA Replication; G1 Phase; Gene Expression; Gene Expression Regulation; Humans; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; S Phase
PubMed: 35173014
DOI: 10.26508/lsa.202201378 -
The American Journal of Pathology Jul 2016Cyclin E and its co-activator, phospho-cyclin-dependent kinase 2 (p-CDK2), regulate G1 to S phase transition and their deregulation induces oncogenesis....
Cyclin E and its co-activator, phospho-cyclin-dependent kinase 2 (p-CDK2), regulate G1 to S phase transition and their deregulation induces oncogenesis. Immunohistochemical assessments of these proteins in cancer have been reported but were based only on their nuclear expression. However, the oncogenic forms of cyclin E (low molecular weight cyclin E or LMW-E) in complex with CDK2 are preferentially mislocalized to the cytoplasm. Here, we used separate nuclear and cytoplasmic scoring systems for both cyclin E and p-CDK2 expression to demonstrate altered cellular accumulation of these proteins using immunohistochemical analysis. We examined the specificity of different cyclin E antibodies and evaluated their concordance between immunohistochemical and Western blot analyses in a panel of 14 breast cell lines. Nuclear versus cytoplasmic staining of cyclin E readily differentiated full-length from LMW-E, respectively. We also evaluated the expression of cyclin E and p-CDK2 in 1676 breast carcinoma patients by immunohistochemistry. Cytoplasmic cyclin E correlated strongly with cytoplasmic p-CDK2 (P < 0.0001), high tumor grade, negative estrogen/progesterone receptor status, and human epidermal growth factor receptor 2 positivity (all P < 0.0001). In multivariable analysis, cytoplasmic cyclin E plus phosphorylated CDK2 (as one variable) predicted breast cancer recurrence-free and overall survival. These results suggest that cytoplasmic cyclin E and p-CDK2 can be readily detected with immunohistochemistry and used as clinical biomarkers for aggressive breast cancer.
Topics: Adult; Aged; Aged, 80 and over; Animals; Biomarkers, Tumor; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Nucleus; Cyclin E; Cyclin-Dependent Kinase 2; Cytoplasm; Female; Humans; Immunohistochemistry; Mice; Mice, Transgenic; Middle Aged; Tissue Array Analysis
PubMed: 27182644
DOI: 10.1016/j.ajpath.2016.02.024