Cyclin D1 protein and CCND1 gene expression in colorectal cancer.

AIMS: To report the expression of cyclin D1 protein and its gene in a series of colorectal adenocarcinoma. METHODS: One hundred and eleven specimens of colorectal carcinomas and adjacent normal colorectal mucosa were investigated by staining with a monoclonal antibody against cyclin D1 and by RT-PCR. RESULTS: Expression of CCND1 gene was found in 54 out of 111 cases of colorectal cancers, while in normal mucosa the expression of this gene was not observed. Cyclin D1 protein expression was checked in the same group of adenocarcinoma cases. Presence of this protein was observed in 69 cases and for 43 of them also expression of its gene was found. Dependence between the presence of protein and the gene expression was statistically significant (p=0.0002). In the group of cases where CCND1 gene expression was detected, high level of its protein expression was found in 20 cases. The CCND1 gene expression was associated with metastases to lymph nodes (p=0.0181) and also with distant metastasis (p=0.0204). CONCLUSIONS: The combined measurement of both the gene and its protein product, is an important contribution to the study of molecular markers in histological material.     

Cyclin D1 protein expression and function in human breast cancer

Cyclin D1 is a cell-cycle regulator essential for G₁, phase progression and a candidate proto-oncogene implicated in pathogenesis of several human tumour types, including breast carcinomas. In spite of the accumulating genetic evidence, however, there are no data regarding abundance and properties of the cyclin D1 protein in breast cancer. We now report aberrant nuclear overexpression/accumulation of the cyclin D1 protein in about half of the 170 primary breast carcinoma specimens analyzed by monoclonal antibody immunohistochemistry, indicating that the frequency of cyclin D1 abnormalities may be considerably higher than previously deduced from DNA amplification studies. A comparison of the expression patterns in matched lesions at different stages of tumour progression revealed that the cyclin D1 protein aberration appears to reflect a relatively early event and that, when acquired by a tumour, it is maintained throughout breast cancer progression including metastatic spread. In both tumour tissues and breast cancer cell lines, the abundance of this protein shows characteristic variations consistent with a cell-cycle oscillation and the peak levels expressed in G₁. In all 7 cell lines whose retinoblastoma (Rb) protein is mutant or complexed to SV40 T antigen, exceptionally low levels of cyclin D1 protein and mRNA were found. Antibody-mediated and anti-sense oligonucleotide knockout experiments demonstrate the requirement for the cell-cycle regulatory function of cyclin D1 in breast cancer lines with single or multiple copies of the gene and reveal the absence of such a requirement in the cell lines with Rb defects. Our data are consistent with the notion that the emerging “Rb-cyclin D1 pathway” represents a frequent target of oncogenic abnormalities in breast cancer. © 1994 Wiley-Liss, Inc.     

Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma

Cyclin D1 (CCND1) plays a key role in cell cycle control, particularly in the transition from G1 to S phase, which is regulated by cyclin-dependent kinases. A common adenine to guanine polymorphism (A870G) in the CCND1 gene has been associated with a longer-life protein and an increased risk of colorectal cancer and adenoma in some studies. Among subjects with hereditary nonpolyposis colorectal cancer, the A870G polymorphism has also been associated with a younger age of onset of colorectal cancer. We analysed 181 colorectal cancer cases and 475 matched controls and 524 adenoma cases and 517 matched controls within women in the Nurses' Health Study (NHS) cohort, 171 colorectal cancer cases and 347 matched controls and 372 adenoma cases and 712 matched controls nested within men in the Health Professionals' Follow-Up Study (HPFS) cohort, and 258 colorectal cancer cases and 415 matched controls within men in the Physicians' Health Study (PHS) cohort to assess the risk associated with the CCND1 A870G genotype. Moreover, we assessed whether CCND1 genotype modified the effect of a sporadic (nonsyndromic) family history of colorectal cancer as well as the effect of other dietary and lifestyle risk factors for colorectal cancer and adenoma. In all cohorts combined, the CCND1 polymorphism did not show statistically significant associations to risk of colorectal cancer (odds ratio (OR) for A allele carriers, 1.04; 95% confidence interval (95% CI), 0.82-1.32) or adenoma (OR, 0.96; 95% CI, 0.79-1.18). The CCND1 A870G genotype was associated with a modest, although nonsignificantly elevated risk of colorectal cancer (OR, 1.59; 95% CI, 0.98-2.57) in women. In contrast, the polymorphism was not associated with increased risk of adenoma in either men or women. Among participants with the A870G genotype, a family history of colorectal cancer conferred a substantially greater risk of colorectal cancer in the women (P for interaction=0.06) and adenoma in the men (P for interaction=0.02). Current postmenopausal hormone (PMH) use was associated with a significant reduction in the risk of colorectal cancer and adenoma among women with the A870G genotype, whereas there was no effect of PMH use among those with the GG genotype. The CCND1 polymorphism appeared to confer a modest elevation in the risk of colorectal cancer among women. Moreover, the A870G genotype may enhance the protective effect of postmenopausal oestrogen use on the development of colorectal neoplasia.     

Cyclin D1 gene polymorphism and susceptibility to lung cancer in a Chinese population

The objective was to study the relationship between cyclin D1 gene (CCND1) polymorphism and lung cancer in the Chinese population. Blood samples of 182 cases and 185 controls were collected from a hospital based case-control study. PCR-SSCP was used to examine the G/A polymorphism in exon 4 of CCND1. The results showed that the frequencies of the CCND1 AA, GA and GG genotypes were 31.3, 46.7 and 22.0% respectively in cases, and 21.1, 53.0 and 25.9 respectively in controls. Adjusted by age (in years), sex and smoking status, multivariate logistic regression analysis showed that the AA genotype was associated with a significantly increased risk (OR = 1.87, 95% CI 1.01-3.45) for lung cancer. In the stratification analysis, the CCND1 AA variant genotype was associated with increased risk in individuals who were 相似文献   

Effects of PEG-liposomal oxaliplatin on apoptosis, and expression of Cyclin A and Cyclin D1 in colorectal cancer cells

Oxaliplatin is one of the agents used against colorectal cancer. Using PEG-liposome encapsulated oxaliplatin may enhance the accumulation of drugs in tumor cells, inducing apoptosis. However, the mechanism of action of PEG-liposome encapsulated oxaliplatin remains unclear. SW480 human colorectal cancer cells were treated with empty PEG-liposomes, free oxaliplatin or PEG-liposomal oxaliplatin. Cell cycle and apoptosis were assessed using fluorescence confocal microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick-end-labeling (TUNEL). Western blotting was used to analyze the expression of pro-apoptotic, anti-apoptotic and cyclin proteins. We found that PEG-liposomal oxaliplatin induced a stronger apoptotic response than empty PEG-liposomes or free oxaliplatin. Moreover, expression of Cyclin D1 increased, whereas expression of Cyclin A decreased after treatment with PEG-liposomal oxaliplatin. Furthermore, the cell cycle was arrested in the G1 phase. The results presented here indicate that PEG-liposome entrapment of oxaliplatin enhances the anticancer potency of the chemotherapeutic agent. The effect of PEG-liposomal oxaliplatin on apoptosis of SW480 human colorectal cancer cells may be through regulation of expression of Cyclin A or Cyclin D1, as well as pro-apoptotic and anti-apoptotic proteins.     

Cyclin D1 protein expression in mantle cell lymphoma

BACKGROUND: The t(ll;14)(ql3;q32) is a chromosomal abnormality usually associatedwith mantle cell (centrocytic) lymphomas, although it has occasionallybeen reported in other chronic lymphoproliferative disorderssuch as chronic lymphocytic leukemia, prolymphocytic leukemia,splenic lymphoma with villous lymphocytes, and multiple myeloma.This abnormality results in the translocation of the bcl-1 oncogenefrom chromosome 11 to the immunoglobulin heavy chain locus onchromosome 14. The bcl-1 oncogene is a member of the cyclingene family, and high levels of cyclin Dl mRNA are consistentlyfound in malignant B cell proliferations with t(ll;14). PATIENTS AND METHODS: We examined cyclin D1 protein expression in 33 patients withlow grade lymphoproliferative disorders and 2 patients withreactive hyperplasias by Western blot analysis using a polyclonalantibody. RESULTS: 8/11 mantle cell lymphomas, 0/11 chronic lymphocytic leukemias,0/4 hairy cell leukemias, 0/2 Sezary syn-drome, 0/2 monocytoidB-cell lymphomas, 0/3 follicular lymphomas, and 0/2 reactivehyperplasias had overexpres-sion of cyclin Dl. Cytogenetic analysiswas performed in four cases of mantle cell lymphoma; three ofthese cases had the t(ll;14), one of which was hypotetraploidwith two copies of t(ll; 14). Immunophenotypically, all casesof mantle cell lymphoma and chronic lymphocytic leukemia hadcoexpression ofCD5 and CD20. CONCLUSION: Mantle cell lymphoma may be difficult to discriminate from chroniclymphocytic leukemia, a more indolent disease, on morphologicand immunophenotypic grounds. Our findings suggest that analysisof cyclin Dl protein expression may be helpful in differentiatingmantle cell lymphomas from other low grade lymphoproliferativedisorders. cyclin D1, bcl-1, mantle cell lymphoma, centrocytic lymphoma, t(ll;14)(ql3;q32), low grade lymphoproliferative disorders     

Cyclin D1 protein overexpression and gene amplification in benign breast tissue and breast cancer risk.

Cyclin D1 amplification and/or protein overexpression have been observed not only in breast cancer but also in the putative early stages of breast neoplasia. In a case-control study nested within a cohort of 4888 women, we investigated whether the occurrence of cyclin D1 gene amplification and/or protein overexpression in benign breast tissue might identify women at increased risk of subsequent breast cancer development. Cases were 92 women with a histological diagnosis of benign breast disease who subsequently developed breast cancer. Five controls (women with benign breast disease who had not developed breast cancer by the date of diagnosis of the corresponding case) were selected randomly for each case from those non-cases available within strata defined by screening centre, National Breast Screening Study (NBSS) study arm, year of birth and age at diagnosis of benign breast disease. Paraffin blocks of benign tissue were suitable for immunostaining for 71 cases and 293 controls. Sufficient DNA for analysis was obtained from a total of 356 subjects (69 cases, 287 controls). The benign breast tissues and breast cancers were immunostained for cyclin D1 and also analysed for the presence of cyclin D1 gene amplification by differential polymerase chain reaction (PCR). Fifteen cases and 60 controls showed evidence of cyclin D1 immunostaining, and 12 cases and 29 controls showed cyclin DL gene amplification. There was essentially no association between cyclin D1 protein overexpression in benign breast tissue and risk of subsequent breast cancer (adjusted odds ratio (OR) 1.06; 95% confidence interval (CI) 0.56-2.02). After adjustment for potential confounding, there was a statistically non-significant 40% increase in risk of breast cancer in association with cyclin D1 gene amplification (adjusted OR 1.41; 95% CI 0.62-3.22). As multiple genetic changes are required to develop breast cancer, it may not be until the cascade of molecular alterations leading to breast cancer development is understood that identification of biomarkers of breast cancer risk will be possible.     

细胞周期蛋白D1基因G870A 多态性与结直肠癌易感性的系统评价

 目的 综合评价细胞周期蛋白D1(Cyclin D1) 基因G870A多态性与结直肠癌易感性的关系.方法通过CNKI、PubMed、EMCC等数据库检索文献,获得有关Cyclin D1基因G870A多态性与结直肠癌危险性关系的研究结果,并通过Meta分析进行系统评价。所有文献均采用病例对照研究或者巢式病例对照研究,以OR值为效应指标, 基因型在对照群体中的分布均符合Hardy Weinberg 遗传平衡定律,对文献进行评价筛选、异质性检验。本次Meta分析共纳入23项研究,累计病例6 344例,对照9 018例,利用RevMan5.0对各研究原始结果进行统计处理, 对突变纯合子AA 和杂合子GA 基因型与纯合基因型GG 进行比较,并计算合并OR值及其95%可信区间(CI）。结果 AA和GA与GG基因型在病例组与健康对照组之间差异有统计学意义,OR= 1.10（95%CI：1.01～1.19, P=0.02）;按不同人群进行分层分析,亚洲人群OR= 1.11（95%CI：0.98～1.26, P=0.11）,美洲人群OR= 1.13（95%CI：0.97~1.32,P=0.12),欧洲人群OR= 1.06（95%CI：0.89～1.25, P=0.52）,大洋洲人群OR= 1.05（95%CI：0.80～1.38, P=0.73）;按不同对照进行分组分析,医院基础OR= 1.07（95%CI：0.95～1.20, P=0.28）,人群基础OR= 1.13（95%CI：1.01~1.26, P=0.04）。结论 Cyclin D1基因G870A 多态性与结直肠癌易感性总体分析在统计学上具有相关性,按不同人群进行分组分析,都不支持具有相关性;按不同对照进行分组分析,以医院基础不具有相关性,以人群为基础具有相关性。     

Cyclin D1: polymorphism, aberrant splicing and cancer risk

The cyclin D1 proto-oncogene exercises powerful control over the mechanisms that regulate the mitotic cell cycle, and excessive cyclin D1 expression and/or activity is common in human cancers. Although somatic mutations of the cyclin D1 locus are rarely observed, mounting evidence demonstrates that a specific polymorphism of cyclin D1 (G/A870) and a protein product of a potentially related alternate splicing event (cyclin D1b) may influence cancer risk and outcome. Herein, we review the epidemiological and functional literatures that link these alterations of cyclin D1 to human tumor development and progression.     

Cyclin D1(CCNDl)A870G 基因多态性与保定地区结肠癌的关系

为了探讨cyclin D1(CCNDl)A870G 基因多态性与保定地区结肠癌患者的年龄、性别、高胆固醇血症、家族史、 病理分型、病理分期的关系,我们从200 例保定地区结肠癌患者和200 例保定地区健康体检者的血中提取DNA,用聚合 酶链反应和限制性酶切片段长度多态体分析对提取的 DNA 进行多肽性分析。结果显示,病例组和对照组 AA\ AG\GG 基因 频率无明显差异。高胆固醇及重度吸烟的结肠癌患者GG 基因型频率明显高于其他基因型,有明显差异（P<0.05）,重度 吸烟及高胆固醇血症在健康体检人群中GG 基因型无明显差异（P>0.05）。由此推断高胆固醇血症及吸烟可作为在cyclin D1(CCNDl)A870G 基因多态性中GG 基因型中结肠癌发生的危险因子,遗传因素的结肠癌患者AA 基因型频率明显高于其 他基因型,有明显差异（P<0.05）。由此推断遗传因素可作为在cyclin D1(CCNDl)A870G 基因多态性中AA 基因型中结肠 癌发生的危险因子,这将为进一步研究结肠癌分子生物学的发生机制提供依据。     

Cyclin D1 in breast cancer pathogenesis.

Taking a perspective on available evidence that emphasizes relevance to human disease, cyclin D1 is solidly established as an oncogene with an important pathogenetic role in breast cancer and other human tumors. However, the precise cellular mechanisms through which aberrant cyclin D1 expression drives human neoplasia are less well established. Indeed, emerging evidence suggests that cyclin D1 might act, predominantly or at least in part, through pathways that do not involve its widely accepted function as a cell cycle regulator. Although therapeutic exploitation of the role of cyclin D1 as a molecular driver of breast cancer carries great promise, it is also suggested that direct targeting of the cyclin D1 gene or gene products may prove more successful than approaches that rely on arguably incomplete knowledge of the oncogenic mechanisms of cyclin D1.     

Cyclin D1 gene G870A polymorphism predicts response to neoadjuvant radiotherapy and prognosis in rectal cancer

PURPOSE: To investigate whether CCND1 genetic variations associated with a constitutive nuclear protein may influence either the pathologic response to preoperative RT or the prognosis in a series of rectal cancer patients. METHODS AND MATERIALS: Seventy rectal cancer patients treated by neoadjuvant radiotherapy were included in the study. CCND1 exon 5 mutations were screened, and the G870A polymorphism was assessed for correlation with clinical variables, tumor response, and patient outcome. RESULTS: No exon 5 mutation was found. Concerning the G870A polymorphism, the A/A variant was significantly associated with radiosensitivity (p = 0.022). Moreover, patients harboring the A allele were correlated with a lower risk of local failure (p = 0.017). Also, combination of the G870A polymorphism with the post-therapeutic lymph node status allowed the elaboration of a prognostic index, which accurately distinguished subgroups of patients with predictable recurrence-free (p = 0.003) and overall (p = 0.044) survival. CONCLUSIONS: Although CCND1 exon 5 mutations are rare in rectal cancer, G870A polymorphism is a frequent variation that may predict radiosensitivity and prognosis.     

Cyclin D1 expression in breast cancer patients receiving adjuvant tamoxifen-based therapy.

PURPOSE: The objective of our study was to determine the clinical relevance of cyclin D1 expression in hormone receptor-positive breast cancer patients who were treated with tamoxifen-based therapy. EXPERIMENTAL DESIGN: We assessed expression of cyclin D1 in surgical specimens of breast carcinoma by means of immunohistochemistry. Patients had been enrolled in either Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 05 or ABCSG Trial 06 and received tamoxifen as part of their adjuvant treatment. Overall survival and relapse-free survival were analyzed with Cox models adjusted for clinical and pathologic factors. RESULTS: Cyclin D1 was expressed in 140 of 253 (55%) tumors of ABCSG Trial 05 and in 569 of 948 (60%) tumors of ABCSG Trial 06. Expression of cyclin D1 was associated with poor outcome in both cohorts. Overall survival was significantly shorter in patients with cyclin D1-positive tumors compared with patients with cyclin D1-negative tumors [adjusted hazard ratio (HR) for death (ABCSG Trial 05), 2.47; 95% confidence interval (95% CI), 1.08-5.63; P = 0.03; adjusted HR for death (ABCSG Trial 06), 1.78; 95% CI, 1.36-2.34; P < 0.0001]. Relapse-free survival was also shorter in patients with cyclin D1-positive tumors than in patients with cyclin D1-negative tumors [adjusted HR for relapse (ABCSG Trial 05), 2.73; 95% CI, 1.50-4.96; P = 0.001; adjusted HR for relapse (ABCSG Trial 06), 1.52; 95% CI, 1.14-2.04; P = 0.005]. CONCLUSION: Cyclin D1 expression is an independent poor prognostic factor in women with early-stage, hormone receptor-positive breast cancer who received adjuvant tamoxifen-based therapy.     

Cyclin D1 gene (CCND1) mutations in endometrial cancer

Cyclin D1 is frequently overexpressed in human neoplasias by gene rearrangement and amplification, but no mutations in the CCND1 gene have so far been reported. However, in vitro mutagenesis of CCND1 has shown that substitutions affecting threonine 286 residue produced cyclin D1 nuclear accumulation, by interfering with protein degradation and induced neoplastic transformation in murine fibroblasts. To test whether similar genetic changes may occur in vivo, we analysed a series of 60 endometrioid endometrial carcinomas (EECs) for cyclin D1 expression and gene amplification by immunohistochemistry and FISH, respectively. Two of 17 carcinomas showing cyclin D1 expression in more than 5% of neoplastic cells, but without gene amplification, were found to harbor single-base substitutions in CCND1 that changed proline 287 into threonine and serine, respectively. Both cases expressed cyclin D1 in more than 50% of neoplastic cells. Additionally, seven tumors with cyclin D1 overexpression of an independent series of 59 EECs were also analysed, and a 12-bp in-frame deletion that eliminated amino acids 289-292 was detected in one case with cylin D1 expression in more than 50% of neoplastic cells. In contrast, no mutations of the CCND1 gene were detected in a set of breast carcinomas with cyclin D1 overexpression without gene amplification. In summary, our data indicate that mutations of CCND1, which probably render the protein insensitive to degradation, represent a previously unreported mechanism of cyclin D1 overexpression in human tumors in vivo.     

Aurora-A and Cyclin D1 polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer

Polymorphisms in the 2 cell-cycle control genes Aurora A and Cyclin D1 have previously been associated with changes in the age of onset of colorectal cancer in persons harboring germline mutations in DNA mismatch repair genes associated with hereditary nonpolyposis colorectal cancer (HNPCC). In this report, we have genotyped 312 individuals, who all harbored confirmed causative mutations in either hMSH2 or hMLH1, for 2 polymorphisms, one in Aurora A (T91A) and the other in Cyclin D1 (G870A). The results reveal that the previous association with the Aurora A polymorphism could not be confirmed in our larger group of HNPCC patients. The Cyclin D1 polymorphism, however, was associated with a significant difference in the age of disease onset on patients harboring hMSH2 mutations, which was not observed in hMLH1 mutation carriers. A combined analysis of the Aurora A and Cyclin D1 polymorphisms did not reveal any obvious association. In conclusion, it appears that the polymorphic variant of Aurora A does not appear to be associated with variation in colorectal cancer risk in HNPCC, whereas there is a more complex relationship between the Cyclin D1 polymorphism and disease risk in HNPCC.     

Association between Cyclin D1 polymorphism and oral cancer susceptibility: a meta-analysis

Data from several case–control studies on the relation between the Cyclin D1 (CCND1) G870A polymorphism and oral cancer susceptibility implicated conflicting conclusions. Thus, a meta-analysis was performed to derive a more precise evaluation of the association. We searched PubMed and Embase for related studies that had been published in English and eight available studies were finally included in the meta-analysis. Odd ratios (ORs) and 95 % confidence intervals (CIs) were calculated for each study. Our meta-analysis suggested that CCND1 G870A polymorphism was not associated with oral cancer risk (OR _{AA vs. GG}?=?1.08, 95 % CI?=?0.90–1.30, P _{heterogeneity}?=?0.175; OR _{AA + GA vs. GG}?=?1.02, 95 % CI?=?0.91–1.14, P _{heterogeneity}?=?0.781; OR _{AA vs. GA + GG}?=?1.16, 95 % CI?=?0.98–1.36, P _{heterogeneity}?=?0.107; OR _{A vs. G}?=?1.05 95 % CI?=?0.96–1.15, P _{heterogeneity}?=?0.211; OR _{GA vs. GG}?=?0.94, 95 % CI?=?0.82–1.08, P _{heterogeneity}?=?0.935). However, in the subgroup analysis by ethnicity, possible significance among Asian groups was indicated in two genetic models (OR _{AA vs. GA + GG}?=?1.27, 95 % CI?=?1.05–1.54, P _{heterogeneity}?=?0.572; OR _{allele A vs. allele G}?=?1.11, 95 % CI?=?1.00–1.24, P _{heterogeneity}?=?0.211). Taken together, the meta-analysis revealed that CCND1 G870A polymorphism might be correlated with the susceptibility of oral cancer in Asians.