595

CCND1

cyclin D1;CCND1;cyclin D1

B-cell CLL/lymphoma 1|B-cell lymphoma 1 protein|BCL-1 oncogene|G1/S-specific cyclin-D1|PRAD1 oncogene

11q13

protein-coding

AIM: Invasive urothelial carcinoma of the bladder (UCB) is characterized by alterations in cell-cycle regulatory pathways. Defects in the expression of cyclin D1, a key cell-cycle regulator, have been implicated in progression of various types of cancer. In the present study, we investigated whether cyclin D1 expression is associated with clinicopathological parameters and whether it has any potential prognostic value in determining risk of UCB recurrence. PATIENTS AND METHODS: Tissue microarrays containing bladder cancer specimens (n=212) and adjacent normal bladder tissues (n=131) were immunostained using an antibody against cyclin D1. The association between cyclin D1 and clinicopathological parameters including stage, lymph node metastasis, and disease-free survival, were evaluated. Cyclin D1 mRNA expression data from human normal bladder (n=14) and cancer specimens (n=28) were extracted from the public Oncomine database. RESULTS: Cyclin D1 mRNA and protein expression were significantly higher in UCB compared to adjacent non-malignant bladder tissue (for mRNA p=0.003, for protein p=0.001). Cyclin D1 protein expression was significantly higher in non-invasive tumors than in muscle-invasive UCB (p=0.016). Among patients with muscle-invasive UCB, increased cyclin D1 expression in tumor cells significantly correlated with lymph node metastasis (p<0.001), and there was a trend of cyclin D1 together with lymph node positivity to be associated with disease recurrence (p=0.678). Loss of nuclear cyclin D1 expression in tumor cells was likewise significantly associated with the presence of lymph node metastasis (p<0.001). CONCLUSION: Altered expression of cyclin D1 is associated with lymph node metastasis and risk of UCB recurrence. Cyclin D1 expression may therefore have clinical value as a prognostic marker and potential therapeutic target.

PURPOSE: Single nucleotide polymorphisms (SNPs) in DNA repair and cell cycle control genes may alter protein function and therefore the efficacy of DNA damaging chemotherapy. We retrospectively evaluated the association of SNPs in DNA repair genes, XRCC1-01 (Arg399Gln) and XRCC3-01 (Thr241Met), and a cell cycle control gene, CCND1-02 (A870G), with progression-free survival (PFS) and breast cancer specific survival (BCSS) in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: SNPs in 95 patients with MBC enrolled onto one of five prospective clinical trials of high-dose chemotherapy and autologous stem-cell transplantation were evaluated using genotyping assays. RESULTS: For XRCC1-01, the hazard ratio (HR) for BCSS was 2.8 (95% CI, 1.60 to 5.00) and the HR for PFS was 2.0 (95%CI, 1.12 to 3.43). For XRCC3-01, the HR for BCSS was 2.0 (95%CI, 1.12 to 3.70) and the HR for PFS was 2.0 (95%CI, 1.09 to 3.59). For CCND1-02, the HR for BCSS was 1.8 (95%CI, 1.12 to 2.78) and the HR for PFS was 1.8 (95%CI, 1.15 to 2.85). Patients carrying one variant genotype (HR, 1.7; 95%CI, 1.07 to 2.82) or combinations of any two variant genotypes (HR, 4.7; 95% CI, 2.41 to 8.94) had significantly poorer BCSS compared with patients carrying zero variants. In multivariable analysis, XRCC1-01, presence of liver metastases, and bone metastases independently predicted BCSS. Combinations of any two variant genotypes were stronger independent predictors of BCSS and PFS than the presence of liver or bone metastases. CONCLUSION: XRCC1-01, XRCC3-01, and CCND1-01 may be predictive of survival outcome in patients with MBC treated with DNA damaging chemotherapy.

BACKGROUND: Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination. PATIENTS AND METHODS: DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate. RESULTS: There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92). CONCLUSION: Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.

Cyclin D1b, a splice variant of the cell cycle regulator cyclin D1, holds oncogenic functions in human cancer. However, the mechanisms underlying cyclin D1b function remain poorly understood. Here we introduced wild-type cyclin D1a or cyclin D1b variant into non-metastatic MCF-7 cells. Our results show that ectopic expression of cyclin D1b promotes invasiveness of the cancer cells in a cyclin D1a independent manner. Specifically, cyclin D1b is found to modulate the expression of alphavbeta3, which characterizes the metastatic phenotype, and enhance tumor cell invasive potential in cooperating with HoxD3. Notably, cyclin D1b promotes alphavbeta3-mediated adhesion and invasive migration, which are associated with invasive potential of breast cancer cells. Further exploration indicates that cyclin D1b makes breast cancer cells more sensitive to toll-like receptor 4 ligand released from damaged tumor cells. These findings reveal a role of cyclin D1b as a possible mediator of alphavbeta3 transcription to promote tumor metastasis.

OBJECTIVE: To evaluate the effects of perioperative total parenteral nutrition on cyclin D1, recurrence and metastasis of colorectal cancer cells. METHODS: A total of 120 patients with colorectal carcinoma were randomly divided into two groups, namely group A(total parenteral nutrition, TPN,60 cases) and group B(non total parenteral nutrition, NTPN, 60 cases). In group A, the patients were given with TPN(including glucose, intralipid, amino acid, and vitamins, etc.) for 10 days perioperation (7 days preoperatively and 3 days postoperatively). In group B, the patients did not receive any nutrition support perioperative nutrition support. The samples were obtained by colonoscopy preoperatively or during operation. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) technique,expression of proliferating cell nuclear antigen (PCNA) by immunohistochemical staining, and the expression of cyclin D1 by in situ hybridization. The apoptotic index (AI), the proliferating index (PI), and the expression of cyclin D1 were calculated perioperatively and postoperatively. RESULTS: After perioperative nutrition support, the expression rates of cyclin D1, PI and AI in group A and group B were (35.23+/-5.12)% and (37.53+/-5.31)%, (7.21+/-2.56)% and (8.75+/-3.84)%, (53.45+/-7.74)% and (56.74+/-8.02)% respectively. There were no significant difference of PI, AI and the expression of cyclin D1(all P>0.05) between two groups. The 3-year recurrent rates in two groups were 16.7% and 15.0%( P>0.05). CONCLUSION: Perioperative TPN can not promote proliferation and apoptosis of carcinoma cells, and has no significant impact on the expression of cyclin D1, recurrence or metastasis of colorectal cancer.

BACKGROUND: Cyclin D1, encoded by the gene CCND1, is a regulatory protein in the cell cycle transition from G(1) phase to S phase. A common polymorphism (A870G) at codon 242 affects splicing of the CCND1 transcript and may cause uncontrollable cellular growth. The present study was performed to test the association between A870G polymorphisms in the CCND1 gene and colorectal cancer risk and progression. PATIENTS AND METHODS: The 870 A>G polymorphism in the cyclin D1 gene was genotyped in a Turkish colorectal cancer case-control population including fifty-seven cases (35 male, 22 female; mean age + or - SD: 59.33 + or - 13.7 years) and 117 controls (63 male, 54 female; mean age + or - SD: 54.4 + or - 12.2 years) using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Genotype frequencies of our patients and controls both confirmed to the Hardy-Weinberg equilibrium. There was no difference in the distribution of CCND1 genotypes and frequencies of the alleles A (59.6% versus 49.6%) and G (40.4% versus 50.4%) in the colorectal cancer patients and controls, respectively. Women homozygous for the cyclin D1 870 GG genotype showed an increased risk for developing colorectal cancer compared to those with the AG+AA genotypes and this result was statistically significant (OR 5.568, 95% CI 1.270-24.417, p=0.02). On the other hand, the cyclin D1 GA genotype was associated with distant metastasis (p=0.016). CONCLUSION: Our findings suggest that genetic variants of A870G might be associated with distant metastasis and also gender.

BACKGROUND: cancer of the gallbladder is a relatively rare neoplasm with a poor prognosis. The exact mechanisms of its genesis are not known and very little information is available on molecular events leading to labeling this as an orphan cancer. MATERIALS AND METHODS: In this prospective case control study we evaluated the expression of p16, pRb and cyclin D1 by immunohistochemistry to study the G1-S cell-cycle check point and its possible role in gallbladder carcinogenesis. A total of 25 patients with gallbladder carcinoma (group I), 25 with cholelithiasis (group II) and 10 normal controls. were enrolled. RESULTS: Cyclin D1 expression was seen in 10 (40%) patients each with carcinoma and cholelithiasis while only in 2 (20%) of the normal gallbladders but differences were not statistically significant (p value=0.488). p16 was expressed in 12% patients of carcinoma of the gallbladder and 28% of cholelithiasis, however this difference was not statistically significant (p value=0.095). Retinoblastoma protein was found to be expressed in 50% of normal gallbladders and 6 (24%) of carcinoma and 8 (32%) of gallstones. The present study failed to demonstrate any conclusive role of cyclin D1/RB/ p16 pathway in carcinoma of the gallbladder. CONCLUSIONS: The positive relation observed between tumor metastasis and cyclinD1 expression and p16 with nodal metastasis suggested that higher cyclin D1/p16 expression may act as a predictive biomarker for aggressive behavior of gallbladder malignancies.

BACKGROUND AND OBJECTIVES: The p16(INK4a) (p16), cyclin D1, cyclin-dependent kinase (CDK) 4 and retinoblastoma (Rb) genes are components of the Rb pathway that controls the G1-S checkpoint of the cell cycle. The aim of this study was to assess the relationship between their abnormalities and clinicopathological features in gastric carcinomas. METHODS: Immunohistochemical analysis of the encoded proteins was performed on a series of 158 cases. RESULTS: Loss of p16/Rb protein (pRb) expression and overexpression of cyclin D1/CDK4 were observed in 49%/40% and 37%/37% of gastric carcinomas, respectively. At least 1 of these abnormalities was found in 86% of the cases and a positive correlation was noted between p16 and pRb (P = 0.009). Cyclin D1 (P = 0.042) and CDK4 (P = 0.008) overexpession was inversely associated with lymph node metastasis and depth of invasion, respectively. Loss of pRb expression was more frequently in diffuse type lesions than in the intestinal type (P = 0.022). The patients with p16+/pRb-/cyclin D1-/CDK4- or p16-/pRb+/cyclin D1-/CDK4- tumors demonstrated particularly poor survival. With multivariate survival analysis, only depth of invasion and TNM stage could be proven as independent predictors. CONCLUSIONS: The Rb pathway is disrupted in the vast majority of gastric carcinomas. This study also identified specific immunohistochemical marker profiles for prognosis.

OBJECTIVE: This study aimed to investigate the expressions and significance of KAI1/CD82 and cyclin D1 in laryngeal squamous cell carcinoma (LSCC). METHODS: Real-time quantitative PCR (Q-PCR) and Western blot assay were employed to detect the expressions of KAI1/CD82 and cyclin D1 in the laryngeal tissues of 86 LSCC patients, 32 patients with laryngeal polyp and 38 patients with laryngeal leukoplakia, and the influence of both proteins on the clinicopathological features and survival of LSCC patients. RESULTS: The changes in mRNA and protein expressions of KAI1/CD82 and cyclin D1 were consistent in three groups, and the expressions of KAI1/CD82 and cyclin D1 were significantly different among three groups (P<0.01 or <0.05). The KAI1/CD82 expression in patients with TNM stage III-IV LSCC, poorly differentiated LSCC, clinical stage III-IV LSCC or lymph node metastasis was markedly lower than that in those with TNM stage I-II LSCC, well differentiated LSCC, clinical stage I-II LSCC or no lymph node metastasis (P<0.01 or <0.05). However, there was no marked difference in KAI1/CD82 expression between males and females and among patients in different age groups (P>0.05). In LSCC patients positive for KAI1/CD82 protein expression, the median survival time was 76 months, which was significantly longer than that in LSCC patients negative for KAI1/CD82 protein expression (48 months; X(2)=16.293, P=0.000). The Cyclin D1 expression in patients with TNM stage III-IV LSCC, poorly differentiated LSCC, or clinical stage III-IV LSCC was dramatically higher than that in patients with TNM stage I-II LSCC, well differentiated LSCC, or clinical stage I-II LSCC (P<0.01 or <0.05). However, no marked difference was noted in cyclin D1 expression between males and females, among patients in different age groups and between patients with and without lymph node metastasis (P>0.05). In LSCC patients positive for cyclin D1 protein expression, the median survival time was 40 months, which was markedly shorter than that in LSCC patients negative for cyclin D1 protein expression (X(2)=9.517, P=0.02). In LSCC patients, there was a negative correlation between KAI1/CD82 expression and cyclin D1 expression (X(2)=7.86, P<0.01). CONCLUSION: KAI1/CD82 affects cell cycle. Both KAI1/CD82 and cyclin D1 are involved in the occurrence and development of LSCC, and may provide clinical information for evaluation of invasiveness, metastasis and prognosis of LSCC. Thus, KAI1/CD82 and cyclin D1 may serve as markers for determination of invasiveness, metastasis and prognosis of LSCC.

OBJECTIVE: To explore the possible relationship between the expressions of macrophage migration inhibitor factor (MIF), cyclin D1, cyclin-dependent kinase 4 (CDK4), phosphorylated-retinoblastoma susceptibility gene product Rb protein (phospho-Rb) and the development of hepatocellular carcinoma (HCC). METHODS: 93 HCC tissues and 5 normal liver tissues were used to investigate the expressions of MIF, cyclin D1, CDK4 and phospho-Rb by tissue microarray and immunohistochemistry methods. RESULTS: The expression rates of MIF, cyclin D1, CDK4 and phospho-Rb in the HCC tissues were 71%, 41%, 82% and 14% respectively, and in the normal liver tissues, they were 0%, 0%, 80% and 20% respectively. The expression rates of MIF and cyclin D1 were significantly different between the tumor and the normal liver tissues and the expression rates of CDK4 and phospho-Rb were not significantly different between the tumor and the normal liver tissues. The rate difference (69% versus 48%) of MIF expression between the larger tumors (> 3.5 cm) and the smaller tumors (< 3.5 cm) was of statistical significance (P < 0.01). The expression rate (62%) of cyclin D1 in the tumors with metastasis was significantly higher than the expression rate (35%) in the tumors without metastasis (P < 0.05). MIF expression was positively correlated with cyclin D1 expression in the tumor tissues (P < 0.01). CDK4 and phospho-Rb expressions were not significantly associated with the tumor sizes and metastasis status. CONCLUSION: Our results indicate that MIF and cyclin D1 might be related to the growth and metastasis of HCC.

The roles of many genes in the pathophysiology of lung cancer have been investigated in different studies. Cyclin D1 (CCND1) gene plays a significant role in the transition from G1 to S phase of the cell cycle and in the phosphorylation of retinoblastoma tumor suppressor protein. In this study, we aimed to identify the relationship between CCND1 A870G gene polymorphism with lung cancer. CCND1 A870G genotypes were determined in 75 patients with lung cancer and in 65 control subjects. DNA was isolated from blood samples and then CCND1 A870G gene polymorphism was identified using PCR and RFLP assay. The distribution of CCND1 A870G polymorphism did not show any significant differences in all lung cancer patients and controls. There was no correlation between CCND1 A870G polymorphism and histopathological findings. However, the AA + AG genotype was significantly higher in metastatic patients, when compared with non-metastatic patients. Thus, the results show that CCND1 gene polymorphism may be a predictor for detecting patients with poor survival who having metastatic disease.

The immunohistochemical expression of cell cycle proteins p16, cyclin D1, and pRb was assessed in 112 benign and malignant melanocytic tumors and correlated with tumor progression, prognosis, and outcome. Comparing benign and malignant tumors, there were significant differences in the median score for all 3 proteins, with decreased p16 (P = .000001), increased cyclin D1 (P = .01), and increased pRb in melanomas (P = .01). There was a progressive loss of expression of p16 with progression from benign naevi to primary melanomas and to metastases. p16 was significantly decreased in primary tumors from melanoma patients who developed recurrent disease (P = .0000013). Cyclin D1 and pRb showed a progressive increase in expression from benign to malignant tumors but with relative decreases in the more advanced tumors (thick primaries and metastatic melanomas). Alterations in cell cycle proteins involved in G1/S transition are implicated in melanocytic tumor progression and have a potential role in diagnosis and prognostication.

Cell migration is essential for developmental morphogenesis, tissue repair, and tumor metastasis. A recent study reveals that cyclin D1 acts to promote cell migration by inhibiting Rho/ROCK signaling and expression of thrombospondin-1 (TSP-1), an extracellular matrix protein that regulates cell migration in many settings including cancer. Given the frequent overexpression of cyclin D1 in cancer cells, due to its upregulation by Ras, Rho, Src, and other genes that drive malignant development, the new findings suggest that cyclin D1 may have a central role in mediating invasion and metastasis of cancer cells by controlling Rho/ROCK signaling and matrix deposition of TSP-1.

BACKGROUND: Pituitary tumors are a common form of endocrine neoplasia. However few studies assessed the expression of the principal cyclin regulating checkpoint exit, cyclin D1. Cyclin D1 expression in pituitary tumors and its possible relation to MIB-1 and p27/Kip1 labeling indices (LIs) was explored. DESIGN: We studied a total of 199 pituitaries, including normal pituitaries (n=7), pituitary adenomas (n=187), and pituitary carcinoma (n=5). All tissues were tested as cores of archived tissue microarrays that were immunostained for cyclin D1, MIB-1 and p27 using a standard technique. Tissue cores were subjected to automated analysis to evaluate the staining LIs. RESULTS: No cyclin D1 positive cells in the normal anterior pituitary gland was found. Sparse nuclear staining was noted in pituitary tumors. Higher expression of cyclin D1 was noted in pituitary carcinomas compared to adenomas (p<0.001), in non-functioning adenomas compared to functioning ones (p<0.001) in macroadenomas versus microadenomas (p=0.017) and in recurrent non recurrent adenomas (p<0.001). Cyclin D1 LI and MIB-1 LI were related among adenomas (p<0.001) and carcinomas (p=0.041). p27 LI was neither related to pituitary adenoma recurrence nor invasion. CONCLUSIONS: expression of cyclin D1 in pituitary tumors is related to cell proliferation, recurrence, and metastatic potential. Nuclear cyclin D1 expression is a good marker of aggressive behavior in pituitary tumors.

OBJECTIVE: To investigate the expression of Pin1, beta-catenin and cyclin D1 in salivary adenoid cystic carcinomas (SACC) and to evaluate the role of beta-catenin and Pin1 in SACC carcinogenesis. METHODS: The expressions of Pin1, beta-catenin and cyclin D1 were examined in the specimens of 65 patients with SACC by immunohistochemistry, and Pin1 protein and mRNA expressions detected by Western blot and RT-PCR in four SACC cell lines. RESULTS: Pin1 was overexpressed in 51 cases of ACC (78%), and 41 (63%) cases showed positive immunoreactivity for cyclin D1 protein in the nuclear fraction in tumor tissues. Fourteen (22%) cases showed positive immunoreactivity for beta-catenin protein in the nuclear/cytoplasmic fraction in tumor tissues, 6 of which exhibited quite evident expression of beta-catenin in nucleolus. The expression of membranous beta-catenin was down-regulated in most of the patients with lymph node metastasis (11/14). CONCLUSIONS: The results suggest that Pin1 and beta-catenin signalling pathway were activated in SACC and might play a pivotal role in SACC carcinogenesis and metastasis.

OBJECTIVE: To evaluate the expression of cell-cycle regulators in papillary thyroid carcinoma in relation to lymph node metastatic features, and to determine whether immunohistochemical staining of cell-cycle markers can predict lymph node metastasis. STUDY DESIGN: Cross-sectional study of prior surgical specimens. SETTING: Academic tertiary referral center. SUBJECTS AND METHODS: We reviewed the clinical records of patients who had undergone surgery for thyroid cancer and follicular adenoma between January 2005 and May 2008 at our clinic. Among these cases, 92 patients, comprising 28 patients with follicular adenoma, 32 with papillary thyroid carcinoma without lymph node metastasis, and 32 with papillary thyroid carcinoma with lymph node metastasis, were selected randomly. Formalin-fixed, paraffin-embedded tissues from the 92 patients were immunohistochemically stained for cyclin D1, cyclin E, p27(kip1), and p57(kip2), and protein expression levels were quantified and compared among the groups. RESULTS: tumor specimens from the papillary thyroid carcinoma group had significantly higher expression levels of cyclin D1 and cyclin E, and cytoplasmic expression of p57(kip2) than the other two groups (P < 0.05). In particular, all malignant cases expressed cyclin D1, and cytoplasmic p57(kip2) was expressed only in malignant cases. Furthermore, differences in the grade of cyclin D1 expression according to lymph node metastasis were statistically significant (P < 0.05). CONCLUSION: Our results suggest that immunohistochemistry of certain cell-cycle regulators may be helpful in the diagnosis of papillary thyroid carcinoma, and that cyclin D1 in particular may be a useful marker for evaluating lymph node metastasis.