Association of cyclin D2 downregulation with adverse prognostic factors and survival: Analysis of D-type cyclins, cyclin E1, p27, and ki-67 mRNA in breast carcinomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22208-e22208
Author(s):  
Helena Brizova ◽  
Marcela Mrhalova ◽  
Roman Kodet
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Regulation ◽  
Mrna Level ◽  
Breast Carcinomas ◽  
Time To Event ◽  
Cyclin D2 ◽  
Ki 67 ◽  
Quantitative Level ◽  
Cycle Regulation

e22208 Background: In a normal mammary gland D-type and E1 cyclins play a significant role in the cell cycle control. Not surprisingly, they are considered to have an oncogenic potential and belong among the most commonly overexpressed genes in breast cancer. Besides, cyclin D2 overexpression is associated with an inhibition of cyclin D1 phosphorylation and with an increase of the p27 inhibitor. Such a complex cell cycle regulation is realized at the quantitative level and results in the proliferation activity control. Therefore, we analyzed the molecules involved in the cell cycle regulation together with the proliferation marker Ki-67 at the quantitative level. Methods: We examined cyclin D1, D2, D3, E1, and p27 and Ki-67 mRNA level by qRT-PCR in 95 fresh frozen invasive ductal breast carcinomas and in 15 non-neoplastic breast tissues. In patients with the carcinoma we correlated the mRNA levels with the ERBB-2 positivity, estrogen and progesterone receptor status, proliferation rate, cyclin D1 protein expression, CCDN1 gene amplification, grade, lymph node status, tumor size and age at diagnosis. We looked for a correlation with overall survival and time to event in 70 patients with available long term follow-up data. Results: The only significant association found in this analysis related to cyclin D2. In comparison with non-neoplastic controls we observed cyclin D2 mRNA down-regulation in breast carcinomas and it was inversely correlated with a higher tumor grade and its greater size, which are considered as parameters related to a less favorable prognosis. Moreover, cyclin D2 mRNA down-regulation together with cyclin D1 and D3 up-regulation revealed a significant association with decreased overall survival and time to event in multivariate analysis. Conclusions: The data indicate that down-regulated cyclin D2 mRNA correlates with a greater malignant potential of breast carcinoma. Thus, establishing cyclin D2 mRNA level may be used as a prognostically relevant investigation and along with other prognostically related data it has a potential in helping to identify patients with an adverse prognosis. Support CZ.2.16/3.1.00/24022 and 00064203.

scholarly journals Elucidation of β-Catenin Cyclin D1 Pathway in Oral Squamous Cell Carcinoma

2018 ◽  
Vol 2 (2) ◽  
Keyword(s):  
Cell Cycle ◽  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cyclin D1 ◽  
Squamous Cell ◽  
Cell Cycle Regulation ◽  
Mrna Level ◽  
Wnt Signaling Pathway ◽  
Cycle Regulation

Background: Oral cancer is sixth most common cancer in India with poor overall disease free survival. In last decade major changes in the cancer management has happened but no such advantage has been seen in the survival of oral cancer patients. One major reason for the poor survival of head and neck squamous cell carcinoma (HNSCC) is lack of good predictive and prognostic biomarkers. Different studies have shown that in cancer cells, cell-cycle regulatory protein expression is altered. Cyclin D1 is a key regulatory molecule in cell cycle regulation. Many of the molecular alterations that cause abnormal biologic behaviour of cancer cells are based on aberrations of cell cycle regulation. Studies have demonstrated that Cyclin D1, c-Myc and MMP7 were important target genes of WNT signaling pathway and overexpression of them was highly associated with accumulation of β-Catenin and mutational defects of the WNT signaling pathway in numerous tumor types. Aim: This study was planned to characterize the β-Catenin and Cyclin D1 transcript level expression pattern in oral squamous cell carcinoma (OSCC) samples. Materials and Methods: Expression patterns of β-Catenin and Cyclin D1 were studied in OSCC at the transcript and protein levels by using qRT-PCR and immunohistochemistry (IHC) respectively. χ2, t-tests and ANOVA were used for the statistical analyses. Results: β-Catenin and Cyclin D1 were significantly overexpressed in oral squamous cell carcinoma cases when compared to normal. Correlation regression analysis showed the expression of Cyclin D1 and β-Catenin at mRNA level were positively correlated. Further, in immunohistochemical analysis β-Catenin showed cytoplasmic staining rather than nuclear. Conclusion: It is concluded that β-Catenin and Cyclin D1 mRNA level analysis using Real-time PCR could serve as biomarkers in oral squamous cell carcinoma since their expression is consistently altered in majority of the oral squamous cell carcinoma samples.

scholarly journals Whole Blood Transcriptome Profiling Identifies DNA Replication and Cell Cycle Regulation as Early Marker of Response to Anti-PD-1 in Patients with Urothelial Cancer

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4660
Author(s):  
Sandra van Wilpe ◽  
Victoria Wosika ◽  
Laura Ciarloni ◽  
Sahar Hosseinian Ehrensberger ◽  
Rachel Jeitziner ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Whole Blood ◽  
Clinical Benefit ◽  
Cell Cycle Regulation ◽  
Urothelial Cancer ◽  
Transcriptome Profiling ◽  
Ki 67 ◽  
Cycle Regulation ◽  
Blood Transcriptome

Although immune checkpoint inhibitors improve median overall survival in patients with metastatic urothelial cancer (mUC), only a minority of patients benefit from it. Early blood-based response biomarkers may provide a reliable way to assess response weeks before imaging is available, enabling an early switch to other therapies. We conducted an exploratory study aimed at the identification of early markers of response to anti-PD-1 in patients with mUC. Whole blood RNA sequencing and phenotyping of peripheral blood mononuclear cells were performed on samples of 26 patients obtained before and after 2 to 6 weeks of anti-PD-1. Between baseline and on-treatment samples of patients with clinical benefit, 51 differentially expressed genes (DEGs) were identified, of which 37 were upregulated during treatment. Among the upregulated genes was PDCD1, the gene encoding PD-1. STRING network analysis revealed a cluster of five interconnected DEGs which were all involved in DNA replication or cell cycle regulation. We hypothesized that the upregulation of DNA replication/cell cycle genes is a result of T cell proliferation and we were able to detect an increase in Ki-67+ CD8+ T cells in patients with clinical benefit (median increase: 1.65%, range −0.63 to 7.06%, p = 0.012). In patients without clinical benefit, no DEGs were identified and no increase in Ki-67+ CD8+ T cells was observed. In conclusion, whole blood transcriptome profiling identified early changes in DNA replication and cell cycle regulation genes as markers of clinical benefit to anti-PD-1 in patients with urothelial cancer. Although promising, our findings require further validation before implementation in the clinic.

scholarly journals Cell cycle regulation of the murine cyclin E gene depends on an E2F binding site in the promoter.

1996 ◽  
Vol 16 (7) ◽  
pp. 3401-3409 ◽  
Author(s):  
J Botz ◽  
K Zerfass-Thome ◽  
D Spitkovsky ◽  
H Delius ◽  
B Vogt ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Binding Site ◽  
Transcriptional Activation ◽  
Cell Cycle Regulation ◽  
Cyclin E ◽  
Mrna Level ◽  
Luciferase Reporter ◽  
Serum Starvation ◽  
E Gene ◽  
Cycle Regulation

Cyclin E controls progression through the G1 phase of the cell cycle in mammalian fibroblasts and potentially in many other cell types. Cyclin E is a rate-limiting activator of cdk2 kinase in late G1. The abundance of cyclin E is controlled by phase-specific fluctuations in the mRNA level; in mammalian fibroblasts, mRNA is not detected under conditions of serum starvation and is accumulated upon serum stimulation, with expression starting in mid-G1. Here, we report the cloning of the murine cyclin E promoter. We isolated a 3.8-kb genomic fragment that contains several transcriptional start sites and confers cell cycle regulation on a luciferase reporter gene. This fragment also supports transcriptional activation by adenovirus E1A, a known upstream regulator of cyclin E gene expression. An E2F binding site which is required for G1-specific activation of the cyclin E promoter in synchronized NIH 3T3 cells was identified in this fragment.

Predictive Markers of Myelodysplastic Syndrome in the Bone Marrow of Patients with Fanconi Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 994-994
Author(s):  
Mohamad M. Al-Rahawan ◽  
Blanche P. Alter ◽  
Barbara J. Bryant ◽  
M. Tarek Elghetany
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Fanconi Anemia ◽  
Cell Cycle Regulation ◽  
Caspase 3 ◽  
Refractory Anemia ◽  
Ki 67 ◽  
Over Expression ◽  
Cycle Regulation

Abstract Fanconi Anemia (FA) patients are at increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Impaired cell cycle regulation may have a role in this predisposition. Over-expression of p53, Ki-67 and survivin proteins has been reported in association with MDS. We analyzed bone marrow samples from 138 individuals: 31 FA, 17 acquired aplastic anemia (AA), 40 sporadic low-grade MDS (MDS-1: 35 refractory cytopenia with multilineage dysplasia [RCMD], 5 RCMD with ring sideroblasts [RCMD-RS]), 11 high-grade MDS (MDS-2: refractory anemia with excess blasts [RAEB]), 12 AML, and 27 normal. To identify cell cycle regulation abnormalities that predict risk of MDS or AML in FA patients, we analyzed bone marrow morphology, cellularity, and immunohistochemical expression of cell cycle regulation proteins: p53 (cycle arrest and apoptosis), Ki-67 (cell proliferation), caspase-3 (apoptosis), and survivin (anti-apoptosis). Protein expression was classified as over-expressed if it was detected in a percentage of cells exceeding the highest values observed in normal marrow. Between group comparisons were made using the Fisher exact test. More FA marrows were hypocellular versus sporadic MDS-1, MDS-2 and AML (p <0.0001 in all). p53 was over-expressed at similar rates in FA, MDS-1, MDS-2 and AML patients (12/25 vs. 22/35, 4/11 and 8/12; p = 0.3, 0.7 and 0.3, respectively); p53 was not over-expressed in AA (0/13, p = 0.003). Ki-67 was also over-expressed at similar rates in FA, MDS-2 and AML patients (9/18 vs. 3/11 and 7/12, p = 0.3 and 0.7), in whom over-expression was higher than in AA or MDS-1 (0/12 and 4/35). Survivin expression was more common in FA than in MDS-1, MDS-2, AML or AA (12/16 vs. 2/32, 0/10, 2/12 or 1/13; p <0.01 for all comparisons). In contrast, the caspase-3 over-expression was higher in MDS-2 than in FA (4/11 vs. 0/18, p = 0.014). 7/31 FA patients had RCMD marrow changes; however, there was no correlation between morphologic features of myelodysplasia and the over-expression of cell cycle markers in these patients. p53 over-expression was frequent in FA, MDS-1, MDS-2, and AML; this distinguishes these disorders from AA. Previous studies found no p53 gene mutations in FA; thus, p53 over-expression observed here may represent upregulation of p53, or diminished p53 protein catabolism. Ki-67 over-expression may be a marker for higher grade MDS. The prevalence of over-expression of survivin was unique to FA, distinguishing it clearly from any of the acquired disorders (AA, MDS or AML), and may be a marker for any inherited bone marrow failure syndrome. Our cell cycle marker results suggest that patients in general in whom there is over-expression of Ki-67 and/or p53 may be at higher risk of evolution to MDS/AML; a longitudinal study is needed to address this prediction.

Control of p21Cip by BRCA1-associated protein is critical for cardiomyocyte cell cycle progression and survival

2019 ◽  
Vol 116 (3) ◽  
pp. 592-604 ◽  
Author(s):  
Cornelia Volland ◽  
Peter Schott ◽  
Michael Didié ◽  
Jörg Männer ◽  
Bernhard Unsöld ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Ki 67 ◽  
Cycle Progression ◽  
Developmental Arrest ◽  
Cycle Regulation ◽  
The Impact

Abstract Aims Identifying the key components in cardiomyocyte cell cycle regulation is of relevance for the understanding of cardiac development and adaptive and maladaptive processes in the adult myocardium. BRCA1-associated protein (BRAP) has been suggested as a cytoplasmic retention factor for several proteins including Cyclin-dependent-kinase inhibitor p21Cip. We observed profound expressional changes of BRAP in early postnatal myocardium and investigated the impact of BRAP on cardiomyocyte cell cycle regulation. Methods and results General knockout of Brap in mice evoked embryonic lethality associated with reduced myocardial wall thickness and lethal cardiac congestion suggesting a prominent role for BRAP in cardiomyocyte proliferation. αMHC-Cre driven cardiomyocyte-specific knockout of Brap also evoked lethal cardiac failure shortly after birth. Likewise, conditional cardiomyocyte-specific Brap deletion using tamoxifen-induced knockout in adult mice resulted in marked ventricular dilatation and heart failure 3 weeks after induction. Several lines of evidence suggest that Brap deletion evoked marked inhibition of DNA synthesis and cell cycle progression. In cardiomyocytes with proliferative capacity, this causes developmental arrest, whereas in adult hearts loss of BRAP-induced apoptosis. This is explained by altered signalling through p21Cip which we identify as the link between BRAP and cell cycle/apoptosis. BRAP deletion enhanced p21Cip expression, while BRAP overexpression in cardiomyocyte-specific transgenic mice impeded p21Cip expression. That was paralleled by enhanced nuclear Ki-67 expression and DNA synthesis. Conclusion By controlling p21Cip activity BRAP expression controls cell cycle activity and prevents developmental arrest in developing cardiomyocytes and apoptosis in adult cardiomyocytes.

scholarly journals Purification, Characterization, and Kinetic Mechanism of Cyclin D1·CDK4, a Major Target for Cell Cycle Regulation

1998 ◽  
Vol 273 (41) ◽  
pp. 26506-26515 ◽  
Author(s):  
Alexandros K. Konstantinidis ◽  
R. Radhakrishnan ◽  
Fei Gu ◽  
R. Nagaraja Rao ◽  
Wu-Kuang Yeh
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Regulation ◽  
Kinetic Mechanism ◽  
Cycle Regulation ◽  
Major Target
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