High Expression Of Cyclin Research Articles

Mediator kinase module proteins, genetic alterations and expression of super-enhancer regulated genes in colorectal cancer.

Genetic alterations are well characterized as contributors to the pathogenesis of cancers. Epigenetic abnormalities can lead to perturbations of the expression of genes in cancer cells without structural defects. Deregulation of proteins of the transcription machinery may result in perturbations of target genes. Mediator, a multiprotein component of the transcription machinery facilitates the function of RNA polymerase II, which transcribes most human genes. A part of the mediator with kinase activity, called the Mediator kinase module shows genetic alterations in a sub-set of colorectal cancers. Data from publicly available genomic series of colorectal cancer patients were examined to determine alterations of Mediator kinase module component genes, including MED12, MED12L, MED13, MED13L, CDK8, CDK19, and CCNC. The prevalence of alterations in genomically defined colorectal cancer sub-sets was also interrogated. The effect of Mediator kinase module member gene expression on colorectal cancer relapse-free survival was investigated. Mutations in genes of the Mediator kinase module were present in a small percentage of colorectal cancers, ranging between 2 to 10% for MED12 and MED13 and alternative units MED12L and MED13L and below 2% for kinases CDK8 and CDK19 and cyclin C. Amplifications of the CDK8 gene were observed in 3% to 5% of colorectal cancers. The highest prevalence of mutations was observed in MSI cancers and the equivalent CMS1 group, with other genomic groups showing much lower frequency. An association of higher expression of MED12 with inferior relapse-free survival was observed. In contrast, higher expression of cyclin C was associated with improved survival. Colorectal cancer cell lines with CDK8 amplifications displayed sensitivity to several small molecule inhibitors of the KRAS/PI3K pathway but not to BET inhibitors. The Mediator kinase module is deregulated in a sub-set of colorectal cancers with differences observed in genomically defined groups. These variations may result in differences in sensitivity to targeted therapies and may have to be taken into consideration as such therapies are developed.

Abstract P2-11-02: BIOMARKERS RELATED TO SURVIVAL BENEFIT IN THE TREATMENT OF METASTATIC LUMINAL BREAST CANCER (mBC) WITH CYCLIN 4/6 INHIBITORS (CDK 4/6i) PLUS ENDOCRINE THERAPY (ET)

Abstract Treatment with CDK4/6i plus ET is the standard treatment for mBC with a significantly better progression free survival (PFS) and a long treatment duration response, although there’s finally a progression. The expression of cyclin E and progesterone receptor had been related to survival, so analyzing of these potential biomarkers could help to select their effect in patients with a long treatment duration (> 20 months). We evaluate 68 mBC treated with CDK4/6I plus ET as a clinical practice in a single institution. Median age was 68 years, 27(39,7%) patients had de novo metastatic disease, 17 (25%) progressed during ET adjuvant, and 24 (35,3%) progressed after 5 years of ET. Forty-eight patients (70%) received CDK4/6I plus ET in first line and visceral disease was present in 40% of patients. The median expression by histoscore with immunohistochemistry of cyclin E (CycE) was 75,3 (4-97) and progesterone receptor (PR) 121. Median PFS was 16 months (8,3- 23,6) with 45 events, 25 months in patients treated in first line and 12 months in second line (p: 0,0001). We analyzed 59 patients who had already completed CDK4/6I plus ET or had achieved a PFS more than 20 months, 40 (69%) in first line and 18 (31%) in second line. We summarized the related of expression of PR, CycE and this combination with PFS more than 20 month. CONCLUSION: Treatment with CDK4/6i plus ET achieved long treatment duration in patients with low expression of cyclin E (OR 3,1 p:0,045), positive progesterone receptor (OR 3,89 p: 0023) and specially in patients with positive progesterone receptor and low expression of cyclin E (OR 7,22 p:0,016). Patients with negative progesterone receptor and high expression of cyclin E had a poor prognosis with a median disease-free survival of 6 months (2.8 – 9.2), so these patients required other treatment approaches to improve their outcomes. Table Citation Format: Serafin Morales Murillo, Ariadna Gasol Cudós, Noemí Tuset Der-Abrain, Izaskun Urdanibia, Alvaro Rodriguez Galindo, Ana Velasco Sánchez, Felip Vilardell Villellas, Douglas Sánchez Guzmán, Carles Canosa Morales, Jordi Melé Olivé, Laura Arbones Cid. BIOMARKERS RELATED TO SURVIVAL BENEFIT IN THE TREATMENT OF METASTATIC LUMINAL BREAST CANCER (mBC) WITH CYCLIN 4/6 INHIBITORS (CDK 4/6i) PLUS ENDOCRINE THERAPY (ET) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-02.

Cyclin H predicts the poor prognosis and promotes the proliferation of ovarian cancer

BackgroundCell cycle dysregulation plays a key role in the pathogenesis of malignant tumors. As a part of the CDK-activating kinase (CAK) trimeric complex, cyclin H is necessary to regulate the cell cycle and proliferation. This investigation aims to characterize the clinical significance and the biological functions of cyclin H in ovarian cancer.MethodsImmunohistochemical staining was performed on 60 ovarian cancer cases, and a correlation between cyclin H expression and the clinical characteristics of ovarian cancer was analyzed. The function of cyclin H in ovarian cancer was further explored using HO8910 cells and a subcutaneous xenograft model of nude mice.ResultCyclin H was slightly expressed in grade 1 ovarian cancer but highly expressed in grade 2 and grade 3 cancerous tissues. The Spearman’s rank correlation analysis showed that the expression of cyclin H is positively correlated with the tumor grade, the FIGO stage, histological grade, and the peritoneal metastasis of ovarian cancer and is also positively correlated with the Ki67 and p-CDK2 in ovarian cancer. Additionally, we found that the five-year survival rate was higher in patients expressing low cyclin H than those expressing high cyclin H. Further, knockdown of cyclin H was achieved using an shRNA in HO8910 ovarian cancer cell line. Silencing cyclin H resulted in a G1/S cell cycle arrest in ovarian cancer cells suppressing its growth. The Ki67 expression was also decreased in cyclin H silenced ovarian cancer.ConclusionThese results suggest that high expression of cyclin H predicts the poor prognosis and promotes the growth of ovarian cancer by regulating the cell cycle.

Potential role of cyclin F mRNA expression in the survival of skin melanoma patients: Comprehensive analysis of the pathways altered due to cyclin F upregulation.

Cyclin F is a part of the Skp, Cullin, F-box containing ligase complex. The activity of cyclin F includes cell cycle control, centrosome duplication and response to DNA damage. The cyclin F expression pattern is very similar to cyclin A, but cyclin F is an orphan cyclin without its cyclin-dependent kinase partner. There is little evidence concerning the role of cyclin F in cancer. In the present study, for the first time, we present analysis from The Cancer Genome Atlas (TCGA) data in the context of expression of cyclin F mRNA in melanoma patients. Our original in silico analysis, not published elsewhere before, revealed that high expression of cyclin F in melanoma patients is associated with worse overall survival. Cyclin F and ribonucleotide reductase family member 2 (RRM2) compose a functional axis responsible for nucleotide metabolism. Impairment in this pathway may contribute to increased DNA damage repair and drug resistance. Additionally, we analyzed the expression of RRM2 mRNA and discovered that high expression of RRM2 is associated with worse overall survival. To shed more light on cyclin F overexpression in melanoma, we analyzed all protein data available in the TCGA melanoma dataset. It was found that in patients with upregulated cyclin F mRNA, we noted increased activity of pathways related to cell cycle and DNA damage repair. These data will support further in vitro and in vivo studies on the involvement of cyclin F in skin cutaneous melanoma.

Molecular characteristics of colorectal neuroendocrine carcinoma; similarities with adenocarcinoma rather than neuroendocrine tumor

To further clarify the molecular features of colorectal neuroendocrine carcinomas (NECs), we immunohistochemically examined tumor samples from 25 NECs, including 9 small cell NECs (SCNECs) and 16 large cell NECs (LCNECs), 20 neuroendocrine tumors (NETs), and 21 poorly differentiated adenocarcinomas (PDCs) for the expression of several biomarkers (p53, β-catenin, Bcl-2, Rb, p16, p21, cyclin D1, and cyclin E) and used sequencing analysis to identify gene alterations of TP53, APC, CTNNB1, KRAS, and BRAF. The frequencies of aberrant p53 expression (88%), β-catenin nuclear expression (48%), and high expression of cyclin E (84%) were significantly higher in NECs than in NETs (0%, 5%, and 5%, P < .01, respectively). The immunohistochemical results of NECs and PDCs were similar. TP53, APC, KRAS, and BRAF gene mutations were variously detected in NECs and PDCs but not in any NETs. The frequencies of decreased expression of Rb (56%) and high expression of p16 (56%) and Bcl-2 (64%) were significantly higher in NECs than in PDCs (5%, 19%, and 5%, P < .05, respectively) or NETs (10%, 5%, and 5%, P < .01, respectively). Such immunohistochemical characteristics of NECs were more evident in SCNECs than in large cell NECs (P < .01). In conclusion, the molecular features of colorectal NECs are similar to those of adenocarcinomas and not to those of NETs. Decreased expression of Rb and high expression of p16 and Bcl-2 are characteristics of NECs, suggesting that Rb-p16 pathway disruption may contribute to the promotion of proliferative activity in colorectal NECs. SCNECs may be a prototype of NECs.

Cyclin E1 is a strong prognostic marker for death from lymph node negative breast cancer. A population-based case-control study

Background. A large proportion of women with lymph node negative breast cancer treated with systemic adjuvant treatment do not benefit from such therapy since the patient is already cured by local treatment. Several studies have suggested that proliferation markers are strong prognostic factors in early breast cancer. Cyclins are probably the most specific markers of cell proliferation. Previously high expression of cyclin E has been associated with breast cancer recurrence.Materials and methods. In this study we investigate the prognostic value of cyclin E1 in node negative breast cancer patients. In a population-based cohort 186 women who died from breast cancer were defined as cases and 186 women alive at the corresponding time as controls. Inclusion criteria were tumour size ≤ 50 mm, no lymph node metastases and no adjuvant chemotherapy. The study was designed to detect an odds ratio of 2.5 with a power of 90% and significance level of 0.05. Cyclin E1 was determined with immunohistochemistry (IHC) on tissue microarray (TMA).Results. High expression of cyclin E1 was significantly associated with breast cancer death, in both uni- and multivariate analyses with odds ratios (OR) 2.3 [univariate, 95% confidence interval (CI) 1.5–3.6] and 2.1 (multivariate, 95% CI 1.2–3.5).Discussion. Cyclin E1 is a strong prognostic factor for breast cancer death in a population-based and node negative patient cohort and can identify high-risk patients in this group.

Cyclin E involved in early stage carcinogenesis of esophageal adenocarcinoma by SNP DNA microarray and immunohistochemical studies.

BackgroundCyclin E is a cell cycle regulator which is critical for driving G1/S transition. Abnormal levels of cyclin E have been found in many cancers. However, the level changes of cyclin E in esophageal adenocarcinoma and its precancerous lesion have not been well studied. Here, we focus on the gene amplification and expression of cyclin E in these lesions, and aim to ascertain the relationship with clinicopathological characteristics.MethodsGenomic DNA was analyzed from 116 esophageal adenocarcinoma and 26 precancerous lesion patients using Affymetrix SNP 6.0 arrays. The protein overexpression of cyclin E was also detected using immunohistochemistry from tissue microarrays containing esophageal adenocarcinoma and precancerous lesions. Patient survival and other clinical data were collected and analyzed. The intensity and percentage of the cyclin E expressing cells in tissue microarrays were scored by two pathologists. Fisher exact tests and Kaplan-Meier methods were used to analyze data.ResultsBy genomic analysis, cyclin E was amplified in 19.0% of the EAC samples. By immunohistochemistry, high expression of cyclin E was observed in 2.3% of squamous mucosa tissues, 3.7% in columnar cell metaplasia, 5.8% in Barrett’s esophagus, 19.0% in low grade dysplasia, 35.7% in high grade dysplasia, and 16.7% in esophageal adenocarcinoma. The differences in cyclin E high expression between neoplastic groups and non-dysplasia groups are statistically significant (p < 0.05). The prognosis for patients with high cyclin E expression appeared slightly better than for those with low cyclin E expression although this was not statistically significant (p = 0.13).ConclusionsThe expression of cyclin E significantly increases from non-dysplasia esophageal lesion to low and high grade dysplasia, suggesting that cyclin E plays an important role in the early stage of carcinogenesis. Importantly, cyclin E is also amplified and highly expressed in a subset of esophageal adenocarcinoma patients, but this increase is not associated with worse prognosis.

High expression of cyclin A is associated with poor prognosis in endometrial endometrioid adenocarcinoma

Cyclins are a group of proteins that act as activators to cyclin-dependent kinases and are required for normal cell cycle transitions. Cyclin A is involved in the transitions between G1 to S and G2 to M. Its deregulation has been linked to a number of neoplasms, including endometrial cancer. The prognostic significance of cyclin A expression seems to be cancer-specific, and current knowledge on its impact on survival of endometrial cancer is limited. This study aimed to investigate the effect of cyclin A expression on cancer-specific survival and its correlation with conventional prognostic factors in endometrioid adenocarcinoma. Biopsies obtained from 211 patients were immunohistochemically stained for cyclin A and differences in expression analyzed at the Oulu University Hospital. Patients were divided into two groups utilizing the ROC curve. Further survival analyses were carried out between these two groups. In this study, we show that cyclin A expression correlates with tumor grade and FIGO stage. We also show that cyclin A is an independent prognostic factor in endometrioid adenocarcinoma. Whether cyclin A plays a role in tumorigenesis or merely is a marker of increased proliferation requires further studies.

Prognostic Impact of Cyclin D1, Cyclin E and P53 on Gastroenteropancreatic Neuroendocrine Tumours

Conventional classifications of gastroenteropancreatic neuroendocrine tumours (GEP- NETs) are rather unsatisfactory because of the variation in survival within each subgroup. Molecular markers are being found able to predict patient outcome in more and more tumours. The aim of this study was to characterize the expression of the proteins cyclin D1, cyclin E and P53 in GEP- NETs and assess any prognostic impact. Tumor specimens from 68 patients with a complete follow-up were studied immunohistochemically for cyclin D1, cyclin E and P53 expression. High cyclin D1 and cyclin E immunostaining (≥ 5% positive nuclei) was found in 48 (71%) and 24 (35%) cases, and high P53 staining (≥ 10% positive nuclei) in 33 (49%) . High expression of P53 was more common in gastric neuroendocrine tumors and related to malignant behavior, being associate with a worse prognosis on univariate analysis (RR=1.9, 95%CI=1.1-3.2). High expression of cyclin E was significantly associated with shorter survival in the univariate analysis (RR=2.0, 95%CI=1.2-3.6) and multivariate analysis (RR=2.1, 95%CI=1.1-4.0). We found no significant correlation between the expression of cyclin D1 and any clinicopathological variables. Our study indicated a prognostic relevance for cyclin E and P53 immunoreactivity. Cyclin E may be an independent prognostic factor from the 2010 WHO Classification which should be evaluated in further studies.

High proliferation is associated with inferior outcome in male breast cancer patients

Assessment of proliferation is important in female breast cancer and individual treatment decisions are based upon its results, especially in the luminal subgroups. Gene expression analyses fail to group male breast cancer into the intrinsic subgroups previously established in female breast cancer. Even though proliferation has been shown to divide male breast cancer into molecular subgroups with different prognoses, the clinical importance of proliferation markers has not yet been elucidated. Previous studies in male breast cancer have demonstrated contradictory results regarding the prognostic impact of histological grade and Ki-67, parameters strongly associated with proliferation. The aim of the present project was to study proliferation in male breast cancer by assessing other proliferation-related markers viz. cyclins A, B, D1 and mitotic count. A total of 197 male breast cancer cases with accessible paraffin-embedded material and outcome data were investigated. Immunohistochemical stainings were performed on tissue microarrays. Kaplan–Meier estimates and the Cox proportional regression models were used for survival analyses with breast cancer death as the event. The subset of patients with high expression of cyclin A (hazard ratio (HR) 3.7; P=0.001) and B (HR 2.7; P=0.02) demonstrated a poorer survival. Furthermore, high mitotic count was associated with an increased risk of breast cancer death (HR 2.5; P=0.01). In contrast, cyclin D1 overexpression was predictive of better breast cancer survival (HR 0.3; P=0.001). In conclusion, high levels of cyclin A and B expression and an elevated mitotic count result in a two to threefold higher risk for breast cancer death, whereas cyclin D1 overexpression halves the risk. The clinical utility of these proliferation markers needs further elucidation.

P85α Regulates Osteoblast Differentiation by Cross-talking with the MAPK Pathway

Class IA phosphoinositide 3-kinase (PI3K) is involved in regulating many cellular functions including cell growth, proliferation, cell survival, and differentiation. The p85 regulatory subunit is a critical component of the PI3K signaling pathway. Mesenchymal stem cells (MSC) are multipotent cells that can be differentiated into osteoblasts (OBs), adipocytes, and chondrocytes under defined culture conditions. To determine whether p85α subunit of PI3K affects biological functions of MSCs, bone marrow-derived wild type (WT) and p85α-deficient (p85α(-/-)) cells were employed in this study. Increased cell growth, higher proliferation rate and reduced number of senescent cells were observed in MSCs lacking p85α compare with WT MSCs as evaluated by CFU-F assay, thymidine incorporation assay, and β-galactosidase staining, respectively. These functional changes are associated with the increased cell cycle, increased expression of cyclin D, cyclin E, and reduced expression of p16 and p19 in p85α(-/-) MSCs. In addition, a time-dependent reduction in alkaline phosphatase (ALP) activity and osteocalcin mRNA expression was observed in p85α(-/-) MSCs compared with WT MSCs, suggesting impaired osteoblast differentiation due to p85α deficiency in MSCs. The impaired p85α(-/-) osteoblast differentiation was associated with increased activation of Akt and MAPK. Importantly, bone morphogenic protein 2 (BMP2) was able to intensify the differentiation of osteoblasts derived from WT MSCs, whereas this process was significantly impaired as a result of p85α deficiency. Addition of LY294002, a PI3K inhibitor, did not alter the differentiation of osteoblasts in either genotype. However, application of PD98059, a Mek/MAPK inhibitor, significantly enhanced osteoblast differentiation in WT and p85α(-/-) MSCs. These results suggest that p85α plays an essential role in osteoblast differentiation from MSCs by repressing the activation of MAPK pathway.

High Expression of Cyclin E Increases the Risk for Breast Cancer Death by 2-3 Fold in Node Negative Breast Cancer Patients.

Abstract Background: A large proportion of women with lymph node negative breast cancer treated with chemotherapy do not benefit from such treatment. Several studies have suggested that proliferation markers can identify patients at increased risk for recurrence. However, current international guidelines do not recommend proliferation markers for clinical use due to lack of well-powered studies and standardization of methodology. We wanted to investigate the prognostic value of cyclin E1 in a large population-based study on node negative breast cancer patients.Study Design: In a population-based, case-control study, 190 women who died from breast cancer were defined as cases and 190 women alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size ≤ 50 mm, no lymph node metastases and no adjuvant chemotherapy. The study was designed to detect an odds ratio (OR) of 2.5 with a power of 90% at a significance level of 0.05. Tumor tissue was immunostained for cyclin E1 with a commercial antibody. Statistical analyses were performed for 200 (cyclin E 200) and 500 cells (cyclin E 500) counted, respectively.Results: Cyclin E1 was highly correlated to histologic grade, Ki-67 and cyclins A/B (rs= 0.5-0.6; p&amp;lt;0.001) and inversely correlated to hormone receptors (rs=-0.2--0.3; p&amp;lt;0.001). There was a statistically significant association between cyclin E1 and breast cancer death both in uni- and multivariate (adjusted for tumor size and age) analyses with OR 2.6 -2.7 for cyclin E 200 and OR 2.1-1.9 for cyclin E 500.Conclusions: We found that cyclin E1 is a prognostic factor for breast cancer death in a population-based node negative patient cohort. Patients with tumors expressing high levels of cyclin E have a 2-3 fold increased risk for breast cancer death. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3033.

A study of the expression of Cyclin E and its isoforms in tumor and adjacent mucosa, correlated to patient outcome in early colon cancer

Background. Cyclin E, a key regulator in the cell cycle, is often over-expressed in malignant disease. It can present as full length (FL) and low-molecular-weight (LMW) isoforms. The purpose of this study was to characterize the expression pattern of cyclin E in colon cancer, both in tumor and in macroscopically normal adjacent mucosa. A secondary aim was to study the possible correlation to clinical factors and patient outcome. Material and method. Tumor and mucosa tissue from 114 patients with radically operated, non-metastatic colon tumors were analyzed. The cyclin E expression was measured by Western Blot in the tumor and adjacent mucosa using the antibody targeting C-terminal. The cyclin E expression was correlated to both pathology factors as differentiation grade and to the patient outcome. Results. Cyclin E was detected in both tumor and adjacent mucosa and in both FL and LMW-forms. FL was present in 29 (25.4%) tumors and only in three (2.6%) mucosa samples, the corresponding figures for the LMW-isoforms were 80 (70.2%) and 67 (58.8%). There was no correlation between the cyclin E expression and gender, age, tumor location or tumor pathology. Patients with a high expression of LMW isoforms (p < 0.03) or a high total expression (FL+LMW) (p < 0.006) had higher risks of recurrence and thus a worse survival. Conclusion. Cyclin E is expressed in FL- and LMW-forms in both colon tumors and the macroscopically normal adjacent mucosa. A high expression of cyclin E in tumor was associated with an increased risk of tumor recurrence and a worse outcome. It could be a possible prognostic marker in non-metastatic colon cancer.

Molecular differences between the triple negative tumors of African-American women and white women.

Abstract Abstract #2087 Purpose. We recently reported associations between triple negative tumors (TNTs) and several key cell-cycle proteins. TNTs have also been associated with: 1) younger age and African-American (AA) race, 2) a relative lack of therapeutic targets, and 3) higher recurrence and poorer survival relative to other tumor subtypes. Furthermore, AA women diagnosed with TNTs experience worse outcomes than white women. TNTs are a mixed group of tumors that includes both basal and non-basal types. Markers that could help differentiate tumors with the poorest outcome would be of great use in determing how to effectively treat women with TNT. This study examines whether there are racial differences in key cell-cycle and apoptotic proteins among women with TNTs and could help to identify potential molecular mechanisms underlying racial disparities in these aggressive tumors.&amp;#x2028; Methods. Invasive TNTs from a population-based cohort of 136 Atlanta women (56 AA and 79 white) aged 20–54, diagnosed between 1990 and 1992, were centrally reviewed and immuno-histochemically analyzed for ER, PR, HER2, Bcl2, Cyclins D1 and E, pRb, p16, p21, p27, p53, p130, Ki67, and apoptotic index (AI). Weighted frequency distributions, Chi-square tests, and logistic regression were used to assess racial differences. Age and stage-adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated.&amp;#x2028; Results. Among the 136 women diagnosed with TNTs, AA women were significantly more likely than white women to present at a later stage, with larger tumors, and increased grade, mitotic activity, tumor necrosis, and apoptotic index. AA women were also significantly younger, poorer, and obese. Cell cycle protein differences between AA and white women diagnosed with TNTs included higher expression of Cyclin E [OR = 4.0 (95% CI=1.9, 8.5)], pRB [OR = 2.8 (95% CI=1.6, 4.9)], p16 [OR = 2.2 (95% CI=1.3,3.8)], p21 [OR = 2.0 (95% CI=1.1, 3.5)], AI [OR = 2.1 (95% CI=1.3, 3.9)], and lower expression of p130 [OR = 0.6 (95% CI=0.3, 1.0)].&amp;#x2028; Conclusions. Exclusively among triple negative tumors, we identified racial differences in expression levels of several key cell-cycle and apoptotic related proteins. Combined with other poor prognostic factors, these differences may account for racial disparities in outcome. Future etiologic studies and clinical trials dedicated to TNTs should consider underlying molecular differences. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2087.

Expression of p21WAF1, p27KIP1 and cyclin E in ameloblastoma

To investigate the expression of cyclin E mRNA, p21(WAF1) mRNA and p27(KIP1) protein in human ameloblastoma (AB), and to explore the clinical and biological characteristics of AB. The expression of cyclin E mRNA, p21(WAF1) mRNA and p27(KIP1) protein in 54 cases of human AB were detected by in situ hybridization or immunohistochemistry (SP method). The positive expression rate of cyclin E mRNA in the cytoplasm or cell nucleus of AB was 66.7% (36/54). The expression of cyclin E mRNA increased with AB recurrence and malignant transformation, and the difference of expression among primary AB, recurrent AB, and malignant AB, was statistically significant. The positive expression ratio of cyclin E mRNA in OKC was 50.0% (8/16). The p21(WAF1) mRNA expression in the cytoplasm or cell nucleus of AB decreased, and the positive ratio was 22.6% (12/54) in AB, 37.5% (6/16) in OKC, respectively. The p27(KIP1) protein expression in the cell nucleus of AB was positive in a small number of cases, and the positive rate was 16.7% (9/54) in AB, 6.3% (1/16) in OKC, respectively. The genesis and invasion of AB is associated with the cell proliferation and differentiation, and regulated by the higher expression of cyclin E and the lower expression of p21(WAF1) and p27(KIP1).

Expression and gene amplification of primary (A, B1, D1, D3, and E) and secondary (C and H) cyclins in colon adenocarcinomas and correlation with patient outcome

Background/Aims: Deregulation of cell cycle control is a hallmark of cancer. The primary cyclins (A, B1, D1, D3, and E) are crucial for cell cycle progression. Secondary cyclins (C and...

The prognosis in spindle-cell sarcoma depends on the expression of cyclin-dependent kinase inhibitor p27(Kip1) and cyclin E.

The aim of the present study was to examine the prognostic significance of p27(Kip1) and cyclin E expression in patients with spindle-cell soft tissue sarcomas. In 46 cases of spindle-cell sarcoma including 17 pre-operative biopsy materials, the expression of p27(Kip1) and cyclin E was immunohistochemically examined. The expression of p27(Kip1) decreased in the nuclei of metastatic primary tumor cells (stage IV), whereas the expression of cyclin E increased in those lesions. On univariate analysis, when the expression of p27(Kip1) and cyclin E was analyzed together, patients with spindle-cell sarcoma exhibiting low expression of p27(Kip1) and high expression of cyclin E showed lower distant-metastasis-free survival (DMFS) and overall survival (OS) than those with other combinations of the two parameters (both P < 0.0001). Multivariate analysis revealed that patients with low p27(Kip1) and high cyclin E expression also showed a decrease in DMFS (P = 0.0007, relative risk = 21.3) and OS (P = 0.005, relative risk = 20.8). These results suggest that the combination analysis of p27(Kip1) and cyclin E expression even in biopsy specimens allows the prediction of the clinical behavior of spindle-cell sarcoma.

Relationship of Mcl-1 isoforms, ratio p21WAF1/cyclin A, and Jun kinase phosphorylation to apoptosis in human breast carcinomas

Full length Mcl-1 is an anti-apoptotic protein consisting of two closely migrating 42/40 kDa species. We now investigated the relationship of these isoforms to the expression of cell cycle stimulatory (cyclin A) and inhibitory (p21WAF1) proteins and to the induction of apoptosis in wt p53 MCF-7 and mutant p53 SKBR3 human breast carcinomas. The latter cells exhibited lower 42 kDa Mcl-1, higher expression of cyclin A relative to that of p21WAF1, and apoptosis in response to okadaic acid, a phosphatase 1/2A inhibitor. The proteasome inhibitor MG-115 selectively increased expression of the 40 kDa Mcl-1 isoform and induced p21WAF1, but also promoted preferential apoptosis in SKBR3 cells. Neither okadaic acid nor MG-115 caused comparable effects in MCF-7 cells. However, vanadate or acetyl furanonaphthoquinone induced the 40 kDa Mcl-1 and greater Jun kinase (JNK) phosphorylation without apoptosis-associated PARP fragmentation in MCF-7 cells. Our data suggest that the higher susceptibility of SKBR3 cells to undergo apoptosis may be partly due to their greater proliferative potential (cyclin A), low expression of the anti-apoptotic 42 kDa Mcl-1 isoform, and suboptimal JNK activation in response to stress.

The SYT-SSX1 fusion type of synovial sarcoma is associated with increased expression of cyclin A and D1. A link between t(X;18)(p11.2; q11.2) and the cell cycle machinery.

A recent large multi-centre study convincingly confirmed previous observations that the SYT-SSX1 fusion type, compared to SYT-SSX2, of synovial sarcoma is associated with a worse clinical outcome. Apart from the clinical impact, this fact also suggests (1) that the SYT-SSX fusion gene may influence molecular mechanisms involved in tumour growth and progression; and (2) that the SYT-SSX1 fusion type has a stronger influence on these mechanisms than SYT-SSX2. The nature of the underlying mechanisms is, however, still unknown. In this study we made use of the SYT-SSX1 vs SYT-SSX2 concept to investigate whether major, tumour relevant, and growth regulatory proteins (e.g. cyclins and cyclin-dependent kinases) may be involved. Using Western blotting analysis on 74 fresh, fusion variant-typed, tumour samples from localized synovial sarcoma, we found a significant correlation between SYT-SSX1 and high expression of cyclin A (P=0.003) and D1 (P=0.025). Our data suggest that SYT-SSX may influence the cell cycle machinery, and that the more aggressive phenotype of the SYT-SSX1 variant is due to an accelerated tumour cell proliferation.

Expressions of cell-cycle regulatory gene products in conventional gastric adenomas: Possible immunohistochemical markers of malignant transformation

In 54 lesions of gastric adenomas consisting of 31 low-grade adenomas (LGAs) and 23 high-grade adenomas (HGAs), 28 intramucosal carcinomas (IMCs), and 23 carcinomas invading the submucosa (SMCs), the expression of cell-cycle regulatory gene products (p53, p21/waf1, p27/kip1, and Ki-67) was studied using immunohistochemical techniques. Several lesions were also analyzed by the fluorescence in situ hybridization method. The overexpression of p53 was found in no LGAs and in 9% of HGAs, whereas a considerable number of cases showed an overexpression in IMCs (39%) and SMCs (43%). A reduced expression of p21/waf1 was present in only 4% of HGAs. Superficial eccentric positivity was present in all LGAs and 74% of HGAs, whereas it was present in 46% of IMCs and 4% of SMCs. P53-positive and p21/waf1-negative lesions, which were supposed to have a mutated p53 gene, were observed in no LGAs, in 4% of HGAs, in 11% of IMCs, and in 26% of SMCs. The expression of cyclin E was more frequently present in carcinomas than in adenomas. However, no high expression of cyclin E was observed among the adenomas. A reduced expression of p27/kip1 was encountered more frequently in carcinoma than adenoma. By a semiquantitative evaluation comparing adenoma and carcinoma in the same stomach, the increased degrees of both p21/waf1 and cyclin E were highlighted. A chromosome gain was detected among 7% of the adenomas and 85% of the carcinomas. In conclusion, the expressions of p53, p21/waf1, p27/kip1, and cyclin E were considered to be of great value for estimating the dysplastic progression of gastric adenomas. Especially, various aspects of protein expression, including its distribution and semiquantitative evaluation of positive cells, and a combined analysis with several proteins, may thus be useful as possible markers of dysplastic evolution in gastric adenomas.