PURPOSE: Cyclins are groups of proteins that play a role as a major regulator of the G1 restriction point promoting inactivation of the retinoblastoma protein. The cyclin D1 gene, CCND1, is amplified in approximately 20% of breast carcinomas and the protein is reportedly overexpressed in 60~80% of all cases. Cyclin D1 overexpression was strongly correlated to estrogen receptor positivity and better histologic grade in breast cancer. The aim of this study was to correlate cyclin D1 overexpression using a well characterized antibody with estrogen receptor status and other clincopathologic parameters. METHODS: From March 1989 to December 1994, 85 patients with primary breast carcinoma were the subject in this study. We analyzed cyclin D1 expression by immnohistochemical staining using cyclin D1 antibody, cells were considered positive according to distinct nuclear staining. The correlation between cyclin D1 expression was compared with important clinicopathologic parameters (tumor size, axillary lymph node status, p53 expression, c-erbB2 expression, histologic grade, estrogen receptor status). RESULTS: Cyclin D1 expression was detected in 37 cases (43.5%). Cyclin D1 expression was high in patients with tumors that expressed estrogen receptor (58.5% vs 26.5%, P=0.019). Cyclin D1 was mainly overexpressed in the histologic grade I and II (75.0%), as compared with 65.2% in cyclin D1 negative tumor, however there was no statistical significance (P=0.067). There were no significant correlation with tumor size, axillary lymph node status, p53 expression, or c-erbB2 expression (P>0.05). CONCLUSION: Cyclin D1 expression in estrogen receptor (ER) positive patients was significantly higher than that seen in ER negative patients. There was a negative correlation between cyclin D1 and tumor histologic grade, however it was not statistically significant. Tumor size, axillary lymph node status, p53 expression, and c-erbB2 expression were not correlated with cyclin D1.
Breast Neoplasms* ; Breast* ; Cyclin D1* ; Cyclins* ; Estrogens* ; G1 Phase Cell Cycle Checkpoints ; Genes, bcl-1 ; Humans ; Lymph Nodes ; Retinoblastoma Protein

BACKGROUND: The t(11;14)(q13;q32) is known to be one of the most frequent chromosomal abnor-malities found in multiple myeloma (MM). However, studies on t(11;14) in MM have been problemat-ic due to the fact that MM cells proliferate poorly in vitro. The purpose of our study is to evaluate inci-dence, clinical, and hematologic findings of MM with IgH and cyclin D1 gene rearrangement and to investigate the usefulness of interphase FISH (fluorescence in situ hybridization). METHODS: The study group included 36 patients (23 newly diagnosed MM, 8 relapsed MM, 5 per-sistent MM after treatment) admitted to Mokdong and Gil Hospital from November 1998 to July 2002. Interphase FISH was performed with IGH/CCND1 dual color, dual fusion translocation probe (Vysis Inc, Downers Grove, IL USA), using bone marrow mononuclear cells. RESULTS: Incidence of IgH and cyclin D1 gene rearrangement by interphase FISH was 19%. One patient with normal karyotype and another patient without any metaphase cells showed IgH and cyclin D1 gene rearrangement with interphase FISH. The lambda light chain subtype was more frequently found in patients with rearrangement (4/5, 80%) than those without rearrangement (6/23, 26%) (P<0.05). No significant differences were found in other clinical and hematologic findings in the two groups. CONCLUSIONS: We suggest that MM with IgH and cyclin D1 gene rearrangement is associated with the expression of lambda light chain. Interphase FISH may be helpful in samples with normal karyotype or no metaphase cells for detection of gene rearrangement of MM.
Bone Marrow ; Cyclin D1* ; Cyclins* ; Gene Rearrangement ; Genes, bcl-1* ; Humans ; Incidence ; Interphase* ; Karyotype ; Metaphase ; Multiple Myeloma*

PURPOSE: Cyclins are groups of proteins that play a role as a major regulator of the G1 restriction point promoting inactivation of the retinoblastoma protein. The cyclin D1 gene, CCND1, is amplified in approximately 20% of breast carcinomas and the protein is reportedly overexpressed in 60~80% of all cases. Cyclin D1 overexpression was strongly correlated to estrogen receptor positivity and better histologic grade in breast cancer. The aim of this study was to correlate cyclin D1 overexpression using a well characterized antibody with estrogen receptor status and other clincopathologic parameters. METHODS: From March 1989 to December 1994, 85 patients with primary breast carcinoma were the subject in this study. We analyzed cyclin D1 expression by immnohistochemical staining using cyclin D1 antibody, cells were considered positive according to distinct nuclear staining. The correlation between cyclin D1 expression was compared with important clinicopathologic parameters (tumor size, axillary lymph node status, p53 expression, c-erbB2 expression, histologic grade, estrogen receptor status). RESULTS: Cyclin D1 expression was detected in 37 cases (43.5%). Cyclin D1 expression was high in patients with tumors that expressed estrogen receptor (58.5% vs 26.5%, P=0.019). Cyclin D1 was mainly overexpressed in the histologic grade I and II (75.0%), as compared with 65.2% in cyclin D1 negative tumor, however there was no statistical significance (P=0.067). There were no significant correlation with tumor size, axillary lymph node status, p53 expression, or c-erbB2 expression (P>0.05). CONCLUSION: Cyclin D1 expression in estrogen receptor (ER) positive patients was significantly higher than that seen in ER negative patients. There was a negative correlation between cyclin D1 and tumor histologic grade, however it was not statistically significant. Tumor size, axillary lymph node status, p53 expression, and c-erbB2 expression were not correlated with cyclin D1.
Breast Neoplasms* ; Breast* ; Cyclin D1* ; Cyclins* ; Estrogens* ; G1 Phase Cell Cycle Checkpoints ; Genes, bcl-1 ; Humans ; Lymph Nodes ; Retinoblastoma Protein

Neoplastic growth is characterized by alterations of oncogenes and antioncogenes. The interaction between activated oncogenes and functional deletion of antioncogene appears to be the driving force directing normal cells to uncontrolled growth resulting in tumor. In addition to those genes mentioned, other genes controlling the entry of cells into the cell cycle have recently been implicated in cancer development. The overexpression of the cyclin D1 gene, which has been mapped to 11q13, either by gene rearrangement or amplification has been noted in various malignant tumors. The product of the cyclin D1 gene forms a complex with cyclin-dependent protein kinases(CDK4) that governs a key transition in the cell cycle. The relationships between the overexpression of cyclin D1 assessed by immunihistochemistry and the amplification of the cyclin D1 gene by differential polymerase chain reaction(DPCR) using primers for dopamin D2 receptor gene in 13 cases of squamous cell carcinomas of the oral cavity have been studied. The semiquantitative assay of cyclin D1 amplification has been made by cyclin D1/dopamin D2 receptor(CD/DR) ratio. The results were as follows; 1. In the normal tissue and the tumor, the CD/DR ratios were 0.82 and 1.36 respectively. This implicates 1.65-fold amplification of cyclin D1 gene in tumor compared to that in normal tissue. 2. The tumor tissue which showed overexpression of cyclin D1 by immunohistochemistry revealed 2-fold amplification of cyclin D1 compared to the normal tissue. 3. The tumor tissue which showed mild expression of cyclin D1 by immunihistochemistry revealed 1.7-fold amplification of cyclin D compared to the normal tissue. 4. The cyclin D1 was overexpressed in the tumor tissue at the rate of 38%. Above results suggest that cyclin D1 has close correlation with the development of carcinoma in the oral cavity. But further studies were needed to elucidate the carcinogeneic mechanisms by comparative studies among cyclin D1, pRb and p53.
Carcinoma, Squamous Cell* ; Cell Cycle ; Cyclin D ; Cyclin D1* ; Cyclins* ; Gene Rearrangement ; Genes, bcl-1* ; Genes, Tumor Suppressor ; Immunohistochemistry ; Mouth ; Oncogenes ; Polymerase Chain Reaction*

PURPOSE: The effect of cyclin D1 overexpression on breast cancer outcomes and prognosis is controversial, even though amplification of the cyclin D1 gene, CCND1, has been shown to be associated with early relapse and poor prognosis. In this study, we examined the relationship between cyclin D1 overexpression and disease-specific survival (DSS). We also analyzed survival in patients who experienced recurrence. METHODS: We retrospectively analyzed data from patients diagnosed with ductal carcinoma between April 2005 and December 2010. We examined clinicopathologic factors associated with cyclin D1 overexpression and analyzed the influence of cyclin D1 on recurrence-free survival and DSS. RESULTS: We identified 236 patients diagnosed with primary breast cancer who completed all phases of their primary treatment. Cyclin D1 overexpression was significantly associated with longer DSS (5-year DSS, 89.9% in patients without cyclin D1 overexpression vs. 98.9% in patients with cyclin D1 overexpression; p=0.008). Multivariate analysis also found that patients with cyclin D1 overexpressing tumors had significantly longer disease-specific survival than patients whose tumors did not overexpress cyclin D1, with a hazard ratio for disease-specific mortality of 7.97 (1.17-54.22, p=0.034). However, in the group of patients who experienced recurrence, cyclin D1 overexpression was not significantly associated with recurrence-free survival. Cyclin D1 overexpression was significantly associated with increased survival after disease recurrence, indicating that cyclin D1 overexpression might be indicative of more indolent disease progression after metastasis. CONCLUSION: Cyclin D1 overexpression is associated with longer DSS, but not recurrence-free survival, in patients with breast cancer. Longer postrecurrence survival could explain the apparent inconsistency between DSS and recurrence-free survival. Patients with cyclin D1-overexpressing tumors survive longer, but with metastatic disease after recurrence. This information should spark the urgent development of tailored therapies to cure these patients.
Breast Neoplasms* ; Breast* ; Carcinoma, Ductal ; Cyclin D1* ; Cyclins* ; Disease Progression ; Genes, bcl-1 ; Humans ; Mortality ; Multivariate Analysis ; Neoplasm Metastasis ; Prognosis ; Recurrence* ; Retrospective Studies

BACKGROUND: beta-Catenin has dual functions: adhesive molucule and transcriptional activator. Subcellular accumulation of beta-catenin and subsequent formation of beta-catenin- Tcf/Lef-1 complexes, as well as c-myc and cyclin D1 genes which were recently defined as target genes of beta-catenin- Tcf/Lef-1, has been shown to be important in the development of colorectal and breast carcinomas. The author investigated the rate of subcellular accumulation of beta-catenin and overexpression of c-myc and cyclin D1, and also investigated the association between them in the pulmonary adenocarcinomas. METHODS: Fifty-one surgically resected primary adenocarcinomas of the lung, including 11 bronchioloalveolar carcinomas, were investigated by immunohistochemical analysis with monoclonal antibodies specific for beta-catenin, c-myc and cyclin D1. Clinico-pathological information were collected from the patient charts and surgical pathology reports. RESULTS: Accumulation of beta-catenin in the nucleus and/or cytoplasm and overexpression of c-myc and cyclin D1 were observed to be 20%, 37%, 16%, respectively. Ten cases showing accumulated patterns of beta-catenin revealed alternative overexpressions of c-myc (7 cases) and cyclin D1 (3 cases). In nonmucinous tumors, 9 cases showing overexpression of c-myc or cyclin D1 revealed accumulations of beta-catenin. The accumulation of beta-catenin was not statistically related to clinico-pathological parameters. The association between c-myc overexpression and histological subtype of tumors was observed. CONCLUSIONS:It is suggested that the accumulation of beta-catenin is closely associated with tumorigenesis in a minor subset (20%) of peripheral adenocarcinomas of the lung. It is also suggested that transactivation of beta-catenin may closely be associated with the overexpression of c-myc or cyclin D1 in the nonmucinous adenocarcinoma.
Adenocarcinoma* ; Adenocarcinoma, Bronchiolo-Alveolar ; Adhesives ; Antibodies, Monoclonal ; beta Catenin* ; Breast Neoplasms ; Carcinogenesis ; Cyclin D1* ; Cyclins* ; Cytoplasm ; Genes, bcl-1 ; Humans ; Lung ; Pathology, Surgical ; Transcriptional Activation

OBJECTIVETo investigate the effect of antisense cDNA of cyclin D1 on the cyclin D1 gene expression and cell proliferation of human hepatocarcinoma HepG2 cells in vitro.

METHODSPlasmids containing cyclin D1 antisense cDNA were constructed and transfected into HepG2 cells. Their effects on cell proliferation were examined by MTT method, RT-PCR, immunohistochemical means, and flow cytometry.

RESULTSCyclin D1 antisense cDNA significantly inhibited the growth of HepG2 cells. The inhibition peaked at 48 hour after transfection by MTT method. RT-PCR analysis showed that cyclin D1 antisense cDNA down-regulated cyclin D1 at the mRNA levels. Expression level of cyclin D1 protein was also decreased as shown by immunohistochemical studies. Cell-cycle analysis by flow cytometry showed that transfected HepG2 cells were arrested at the G1 phase of the cell cycle.

CONCLUSIONSOur data suggest that cyclin D1 antisense cDNA could specifically inhibit the expression of cyclin D1 mRNA and protein and regulate cell cycle and cell proliferation of HepG2 cells. Cyclin D1 antisense cDNA may serve as a potential antitumor strategy in regulating cell-cyclin treating advanced HCCs.

Carcinoma, Hepatocellular ; metabolism ; pathology ; Cell Line, Tumor ; Cyclin D1 ; genetics ; Genes, bcl-1 ; genetics ; Humans ; Liver Neoplasms ; metabolism ; pathology ; Oligodeoxyribonucleotides, Antisense ; genetics

BACKGROUND: Overexpression of the cell cycle control gene, cyclin D1 may, at least in some tumor types, provide a prognostic marker. Cyclin D1 is expressed during the G1 phase of the cell cycle and becomes associated with its catalytic partner CDK4 or CDK6. This association may overcome the G1 arrest. OBJECTIVES: To establish the frequency of cyclin D1 protein overexpression and to evaluate its correlation with cyclin D1 gene amplification and its correlation with clinico-pathologic variables that are used in clinical practice. MATERIALS AND METHODS: The cyclin D1 gene amplification was estimated with the differential polymerase chain reaction(PCR) and cyclin D1 protein overexpression was evaluated with immunohistochemical study in 32 cases of resectable head and neck squamous cell carcinoma(SCC). The presence or absence of cyclin D1 protein overexpression was correlated with anatomical sites, T stage, nodal involvement, pathologic grade and survival rate. RESULTS: Six SCC cases(18.7%) showed the amplification of cyclin D1 gene. A highly statistical correlation between cyclin D1 gene amplification and cyclin D1 protein overexpression was noted(p<0.05). However in seven cases(21.9%) there was cyclin D1 protein overexpression without gene amplification. There was no correlation between cyclin D1 protein overexpression and known clinicopathologic variables(T and N stages, pathologic grade)(p>0.05). But overexpression of cyclin D1 protein was associated with a poor survival of these cases(p<0.05). CONCLUSIONS: Overexpression of cyclin D1 is the independent prognostic factor for the head and neck squamous cell carcinoma. The cyclin D1 gene amplification results in the overexpression of cyclin D1 protein. But additional genetic mechanisms are involved in the protein overexpression. Therefore, cyclin D1 oncogene may be important in tumorigenesis in the head and neck squamous cell carcinoma.
Carcinogenesis ; Carcinoma, Squamous Cell* ; Cell Cycle ; Cell Cycle Checkpoints ; Cyclin D1* ; Cyclins* ; G1 Phase ; Gene Amplification ; Genes, bcl-1 ; Head* ; Neck* ; Oncogenes ; Survival Rate

To investigate whether the Bcl-2 gene family is involved in modulating mechanism of apoptosis and change of cell cycle protein induced by curcumin in acute myeloid leukemia HL-60 cell line and primary acute myelogenous leukemic cells, the Bcl-2 family member Mcl-1, Bax and Bak and cell cycle proteins including P27kipl, P21wafl, cyclin D3 and pRbp- were selected and their expression detected by SABC immuno-histochemical stain method. The attitude of sub-G1 peak in DNA histogram was determined by FCM. The TUNEL positive cell percentage was identified by terminal deoxynucleotidyl transferase (TdT)-mediated Biotin dUNP end labeling technique. It was found that when HL-60 cells were treated with 25 mumol/L curcumin for 24 h, the expression level of Mcl-1 was down-regulated, but that of Bax and Bak up-regulated time-dependently. There was significant difference in the expression level of Mcl-1, Bax and Bak between the curcumin-treated groups and control group (P < 0.05-0.01). At the same time, curcumin had no effect on progress of cell cycle in primaty acute myelogenous leukemia at newly diagnosis, but could increase the peak of Sub-G1 (P < 0.05), and down-regulate the expression of Mcl-1 and up-regulate the expression of Bax and Bak with the difference being statistically significant. The expression of P27kipl, P21wafl and pRbp- were elevated and that of cyclin D3 decreased in the presence of curcumin. These findings suggested that the Bcl-2 gene family indeed participated in the regulatory process of apoptosis induced by curcumin in HL-60 cells and AML cells. Curcumin can induce apoptosis of primary acute myelogenous leukemic cells and disturb cell cycle progression of HL-60 cells. The mechanism appeared to be mediated by perturbing G0/G1 phases checkpoints which associated with up-regulation of P27kipl, P21wafl and pRbp- expression, and down-regulation of cyclin D3.
Antineoplastic Agents, Phytogenic ; pharmacology ; Apoptosis ; drug effects ; Cell Cycle Proteins ; metabolism ; Curcumin ; pharmacology ; Genes, bcl-2 ; genetics ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute ; pathology ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins ; biosynthesis ; genetics ; Proto-Oncogene Proteins ; biosynthesis ; genetics ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Tumor Cells, Cultured ; bcl-2-Associated X Protein

BACKGROUND: The cyclin D1 gene is one of the most frequently amplified chromosomal regions(11ql3) in human carcinomas. In laryngeal and head and neck carcinomas, its overexpression has been shown to be associated with advanced local invasion and presence of lymph node metastases. Cyclin D1 may therefore play a key role in cell growth regulation and tumorigenesis. Lung cancer is a worldwide problem and in many contries it is the most lethal malignancy. As relapse is frequent after resection of early stage non-small cell lung cancer, there is an urgent need to define prognostic factors. PURPOSE: This study was undertaken to evaluate the prognostic value of the cyclin D1, that is one the G1 cyclins which control cell cycle progression by allowing G1 to S phase transition, on the patients in radically resected non-small cell lung cancer. METHOD: Total Si cases of formalin-fixed paraffin-embedded blocks from resected primary non-small cell 11mg cancer from January 1., 1983 to July 31, 1995 at Hanyang University Hospital were available for both clinical follow-up and immunohistochemical staining using monoclonal antibodies for cyclin D1. RESULTS: The histologic classification of the tumor was based on WHO criteria, and the specimens included 45 squamous cell carcinomas, 25 adenocarcinomas and 11 large cell carcinomas. Cyclin D1 overexpression was noted in 26 cases of 81 cases tested (30.9%). Cyclin D1 expression was not significantly associated with cell types of the tumor, pathological staging and the size of the tumor. But cyclin D1 overexpression was significantly correlated with positive lymph node metastasis(p=0.035). The mean survival duration was 22.76+/-3.50 months in cyclin D1 positive group and 45.38 +/- 5.64 months in cyclin D1 negative group. There was a nearly significant difference in overall survival Between cyclin D1 positive and negative groups(p=0.0515) in radically resected non-small cell lung cancer. CONCLUISON: Based on this study, cyclin D1 overexpressiom appears at important poor prognostic indicator in non-small cell lung cancer and may have diagnostic and prognostic importance in the treatment of resectable non-small cell lung cancer.
Adenocarcinoma ; Antibodies, Monoclonal ; Carcinogenesis ; Carcinoma, Large Cell ; Carcinoma, Non-Small-Cell Lung* ; Carcinoma, Squamous Cell ; Cell Cycle ; Classification ; Cyclin D1* ; Cyclins* ; Follow-Up Studies ; Genes, bcl-1 ; Head ; Humans ; Lung Neoplasms ; Lymph Nodes ; Neck ; Neoplasm Metastasis ; Recurrence ; S Phase