Cyclin D1 overexpression is more prevalent in non-Caucasian breast cancer

African-American women with breast cancer consistently show a shortened survival when compared with Caucasians with breast cancer, however it is not clear whether this is due to socioeconomic factors or to racial differences in tumor biology. Cyclin D1 overexpression has been demonstrated in 60-80% of female breast cancers, however these studies have not included race or ethnicity data. We examined the level of cyclin D1 protein expression in 139 cases of female breast cancer obtained from different ethnic populations. Using an immunoperoxidase-based technique and a polyclonal anti-cyclin D1 antibody, the rate of overexpression was 68%. Cyclin D1 overexpression tended to be more frequent in cases from non-Caucasian patients when compared with those from Caucasian patients (77% vs. 59%, p=0.051). Our findings suggest that non-Caucasian ethnicity may be important in predicting cyclin D1 overexpression. Cyclin D1 could therefore serve as a possible target in managing breast cancer in the African-American population.     

Cyclin D1 overexpression in a model of human breast premalignancy: preferential stimulation of anchorage-independent but not anchorage-dependent growth is associated with increased cdk2 activity

Cyclin Dl is frequently overexpressed in human breast ductal carcinoma in situ (DCIS) specimens, which confer a high risk for the development of infiltrating ductal carcinoma. If causally involved in the genesis of human breast malignancy, cyclin D1 may represent an interesting target for chemopreventive approaches, as it sits at the junction of many growth factor and hormonal pathways. We have used the MCF-10A human breast cell line, derived from a mastectomy containing a low risk premalignant lesion, as a model system. Three cyclin D1 transfectants exhibited physiologically relevant levels of transgene overexpression, but no coordinate overexpression of other cell cycle related genes. Proliferation assays, flow cytometry, and cdk enzymatic assays of anchorage-dependent proliferation indicated only a minimal and transient effect of cyclin D1. In contrast, cyclin D1 overexpression significantly stimulated anchorage-independent colonization in soft agar or methylcellulose, accompanied by greater Gl-S progression. The cdk4 activity of the control- and cyclin D1 transfectants in colonization assays was comparable, but the cdk2 activity was higher in the latter. Injection of control- and cyclin D1 transfected MCF-10A cells in matrigel into nude mice failed to produce tumors within 1.5 years. The data suggest that cyclin D1 overexpression is an early feature of breast neoplastic progression, and can contribute to cancer development through the promotion of colonization.     

Cyclin D1 expression in endometrioid-type endometrial adenocarcinoma is correlated with histological grade and proliferative activity, but not with prognosis

To elucidate carcinogenesis in the endometrium, we investigated cyclin D1 immunoreactivities in 20 normal endometria, 20 endometrial hyperplasias and 141 endometrioid-type endometrial adenocarcinoma. We also evaluated the correlation of cyclin D1 expression with Ki-67, cyclin E, cyclin A, cdk2, p27 and p53, and clinicopathological parameters and prognosis. Cyclin D1 expression increased significantly with histological grade, and the labeling index (LI) for cyclin D1 was 121 +/- 23.4% in G1, 12.7 +/- 23.7% in G2 and 15.7 +/- 18.5% in G3. The LIs were significantly correlated with those for cyclin E, cyclin A and Ki-67, but not with the LIs of cdk2, p27 or p53. In contrast, high cyclin D1 expression was significantly correlated with low p53 expression. Cyclin D1 expression was not significantly correlated with any of the clinicopathological parameters except histological grade. Cyclin D1 expression was significantly correlated with histological grade and proliferative activity, but not clinicopathological parameters and prognosis in endometrial adenocarcinoma.     

Cyclin K and cyclin D1b are oncogenic in myeloma cells

Background  

Aberrant expression of cyclin D1 is a common feature in multiple myeloma (MM) and always associated with mantle cell lymphoma (MCL). CCND1 gene is alternatively spliced to produce two cyclin D1 mRNA isoforms which are translated in two proteins: cyclin D1a and cyclin D1b. Both isoforms are present in MM cell lines and primary cells but their relative role in the tumorigenic process is still elusive.     

Cyclin D1 overexpression as a prognostic factor in patients with esophageal carcinoma.

BACKGROUND AND OBJECTIVES: Cyclin D1 is known to play important roles in the G1/S check-point of the cell cycle. We investigated the correlation between cyclin D1 overexpression and clinical characteristics to clarify its prognostic significance in patients with esophageal cancer. METHODS: From 1991 to 1998, cyclin D1 was investigated in esophageal cancers from 86 patients who underwent esophagectomy. Overexpression of cyclin D1 was demonstrated using an immunohistochemical method. RESULTS: Overexpression of cyclin D1 was found in 23 (26.7%) of 86 cases. Overexpression of cyclin D1 correlated with lymph node metastasis (P = 0.0083) and lymphatic vessel invasion (P = 0.018). Cyclin D1 overexpression may indicate resistance to chemotherapy. The patients with cyclin D1 overexpression had a significantly lower survival rate than those without overexpression (P = 0.013). The multivariate analysis revealed cyclin D1 overexpression to be an important prognostic factor in patients with esophageal cancer. CONCLUSIONS: Immunohistochemical examination of cyclin D1 expression may provide important prognostic information in univariate and multivariate analysis and may be necessary for determining therapeutic strategies for esophageal cancer.     

胰腺癌组织中cyclin D1和rasp21表达的研究

目的 :探讨细胞周期素 (cyclin)D1和rasp2 1蛋白在胰腺癌中的相互关系。方法 :应用免疫组化方法检测cyclinD1和rasp2 1在胰腺癌中的表达。结果 :cyclinD1和rasp2 1在胰腺癌中的阳性表达率分别为60 0 %和 72 5 % ,二者在胰腺癌中的表达差异有统计学意义 ,P <0 0 5。cyclinD1阳性表达与肿瘤的分化程度密切相关 ,P <0 0 5。结论 :cyclinD1和rasp2 1过表达在胰腺癌发生过程中具有协同作用。     

Cyclin D1 overexpression is a negative predictive factor for tamoxifen response in postmenopausal breast cancer patients

Antioestrogen treatment by tamoxifen is a well-established adjuvant therapy for oestrogen receptor-alpha (ERalpha) positive breast cancer. Despite ERalpha expression some tumours do not respond to tamoxifen and we therefore delineated the potential link between the cell cycle regulator and ERalpha co-factor, cyclin D1, and tamoxifen response in a material of 167 postmenopausal breast cancers arranged in a tissue array. The patients had been randomised to 2 years of tamoxifen treatment or no treatment and the median follow-up time was 18 years. Interestingly in the 55 strongly ERalpha positive samples with moderate or low cyclin D1 levels, patients responded to tamoxifen treatment whereas the 46 patients with highly ERalpha positive and cyclin D1 overexpressing tumours did not show any difference in survival between tamoxifen and no treatment. Survival in untreated patients with cyclin D1 high tumours was slightly better than for patients with cyclin D1 low/moderate tumours. However, there was a clearly increased risk of death in the cyclin D1 high group compared to an age-matched control population. Our results suggest that cyclin D1 overexpression predicts for tamoxifen treatment resistance in breast cancer, which is line with recent experimental data using breast cancer cell lines and overexpression systems.     

Cyclin D1 overexpression related to retinoblastoma protein expression as a prognostic marker in human oesophageal squamous cell carcinoma.

The relationship between aberrant expression of cyclin D1 and retinoblastoma (RB) protein and clinicopathological factors was investigated in 80 patients with oesophageal SCC using immunohistochemical analyses. Heterogeneous staining of cancer cell nuclei with antibody to cyclin D1 was found in 31.3% of patients (25 out of 80 patients). Nuclear staining of cancer cells with anti-RB antibody was homogeneous in 10.0% (8 out of 80 patients) and heterogeneous in 58.8% (47 out of 80 patients). Among cases with homogeneous staining for RB protein, 75% (six out of eight patients) exhibited simultaneous positivity for cyclin D1 (P < 0.05). No significant relationship was found between cyclin D1 or RB protein expression and various clinicopathological parameters. The prognosis of patients with cyclin D1-positive tumours was significantly poorer than that of the other patients (P < 0.01). In addition, when patients with cyclin D1-positive and -negative tumours were stratified according to presence or absence of lymph node metastasis and RB status, the cumulative survival rates in the cyclin D1-positive groups were significantly lower for patients without lymph node metastasis (P < 0.01) and for patients whose tumours were positive for RB (P< 0.0001). These findings suggest the possibility that cyclin D1 positivity is a useful prognostic marker related to lymph node metastasis and RB protein expression in human oesophageal SCC, in addition to clinicopathological factors.     

Cyclin D1 overexpression associates with radiosensitivity in oral squamous cell carcinoma.

Overexpression of cyclin D1, a G1 cell cycle regulator, is often found in many different tumor types, including oral squamous cell carcinomas (SCC). Recent laboratory experiments have demonstrated that cyclin D1 levels can influence radiosensitivity in various cell lines. This study evaluated the relationship between cyclin D1 expression levels and radiosensitivity in nine oral SCC cell lines (HSC2, HSC3, HSC4, SCC15, SCC25, SCC66, SCC111, Ca9-22, and NAN2) and 41 clinical patients with oral SCC who underwent preoperative radiation therapy. Radiosensitivity of the nine oral SCC cell lines differed greatly in their response to radiation, assessed by a standard colony formation assay. Likewise, the expression of cyclin D1 varied, and the magnitude of the cyclin D1 expression correlated with increased tumor radiosensitivity. The similar significant association between the response to preoperative radiation therapy and cyclin D1 overexpression was observed in the oral SCC patients who were treated with preoperative radiation therapy. These results suggest that cyclin D1 expression levels correlate to radiosensitivity and could be used to predict the effectiveness of radiation therapy on oral SCC.     

Cyclin D1 is necessary but not sufficient for anchorage-independent growth of rat mammary tumor cells and is associated with resistance of the Copenhagen rat to mammary carcinogenesis

To identify genes associated with the resistance of Copenhagen (Cop) rats to mammary carcinogenesis, we infused a retrovirus harboring v-Ha-ras directly into the main mammary ducts of resistant F1 rats from a cross between Cop and susceptible Wistar Furth (WF) rats. Adenocarcinomas formed in approximately 50% of infused glands. Cell lines derived from these tumors were clonal, but did not share a common viral integration site, suggesting that a high level of v-Ha-ras expression was able to overcome resistance in the F1 rats. Some of the cell lines were able to grow in soft agar, but a significant number did not display anchorage-independent growth. These growth characteristics were independent of v-Ha-ras expression levels. The ability to grow in soft agar was associated with the size of tumors induced by injecting the cells into nude mice, and showed a striking positive association with the expression of cyclin D1. Furthermore, while resistance to anchorage-independent growth was fully overcome by transfection of cyclin D1 in some clones, in the others the effect was partial. A similar pattern of cyclin D1 upregulation and growth in soft agar was also observed when the cells were transfected with an active form of beta-catenin. Hybrid cells from the somatic fusion of an anchorage-dependent to an anchorage-independent clone did not grow in soft agar. These results suggest that while a high expression level of cyclin D1 is necessary for anchorage-independent growth in all clones, it is not sufficient for full growth capacity in soft agar, raising the possibility that the loss of a tumor suppressor gene in the cell lines is required to fully confer anchorage-independent growth. Our anchorage-dependent and -independent rat mammary tumor-derived cell lines may recapitulate the resistance and susceptibility of Cop and WF rats, respectively, to mammary carcinogenesis that could facilitate the identification of breast cancer susceptibility genes.     

Cyclin D1 is a candidate oncogene in cutaneous melanoma

The retinoblastoma pathway has been implicated in melanoma; however, previous studies of one of the key components of this pathway, cyclin D1 (CD1), failed to find amplification of this gene in a large series of melanomas. We have recently shown that a particular subtype of melanoma, acral melanoma (AM), has frequent amplification of the CD1 locus. This suggested that CD1 might be important in AM and that it may also be important in other melanoma types, even though its copy number may not be altered. We compared CD1 gene copy number and protein expression in 137 invasive primary cutaneous melanomas (71 superficial spreading melanomas, 17 nodular melanomas, 19 lentigo maligna melanomas, 18 AMs, and 12 unclassifiable melanomas) using fluorescence in situ hybridization and immunohistochemistry. We found frequent amplification of CD1 in AM (44.4%) and occasional amplification in lentigo maligna melanoma (10.5%) and superficial spreading melanoma (5.6%). CD1 protein was overexpressed in all cases with amplifications and in an additional 20% of cases without amplification. We tested the importance of CD1 in cell growth in melanoma by using adenovirus-mediated antisense treatment targeted to CD1 in two melanoma cell lines, one with and the other without CD1 amplification and overexpression. Antisense mediated down-regulation of CD1 induced apoptosis in vitro and led to significant tumor shrinkage of melanoma xenografts in severe combined immunodeficient mice. However, it did not alter the growth of normal melanocytes. Together, these results suggest that CD1 may be an oncogene in melanoma and that targeting its expression may be therapeutically beneficial.     

Cyclin D1 overexpression correlates with poor prognosis in patients with tongue squamous cell carcinoma

Tongue squamous cell carcinoma makes up a large percentage of head and neck cancers, and the incidence among young patients is increasing. The aim of this study was to reveal the correlation between cyclin D1 (CCND1) expression and clinical and histologic features. We performed an immunohistochemical study on the level of CCND1 expression in tumor specimens obtained from 94 patients with tongue squamous cell carcinoma. The relationship between the expression and the following features such as age, sex, smoking and alcohol intake history, T, N, histologic grade, and multiple primary cancer was analyzed. Eighteen patients (19%) showed CCND1 overexpression (tumor cell nuclei positivity >/=50%). The 5-year survival rate of high CCND1 expressors was 39%, which was significantly poor (p=0.04). N classification correlated with CCND1 expression. CCND1 overexpression is associated with poor survival associated with progression of lymph node spread in patients with tongue squamous cell carcinomas. CCND1 expression may be a useful biologic marker for prognosis.     

Cyclin D1 overexpression is a critical event in gallbladder carcinogenesis and independently predicts decreased survival for patients with gallbladder carcinoma.

This study was designed to test the hypothesis that cyclin D1 overexpression is involved in the multistep process of gallbladder carcinogenesis and can be used to predict poor prognosis for patients with gallbladder carcinoma (GBC). Cyclin D1 expression was examined immunohistochemically in a series of specimens, including 8 normal epithelia, 8 benign adenomyoma lesions, 6 precancerous adenomas, and 37 carcinomas of the gallbladder. Four of the 6 (67%) adenomas and 15 of the 37 (41%) adenocarcinomas demonstrated cyclin D1 overexpression (>5% nuclear staining), whereas all normal epithelia and adenomyoma lesions were negative for cyclin D1. Kaplan-Meier curves showed that cyclin D1 overexpression was significantly related to decreased overall survival (P < 0.05) in patients with GBCs. The Cox proportional hazards model identified cyclin D1 overexpression as an independent prognostic marker for death (P = 0.024; risk ratio, 4.2; 95% confidence interval, 1.2-14.7). To test whether cyclin D1 overexpression is a critical event in gallbladder neoplasms, cyclin-dependent kinase inhibitor p27Kip1 was introduced to ascertain how cyclin D1 affects clinical outcomes. Subsequently, neoplasms were divided into three groups on the basis of the combination of cyclin D1 expression and p27Kip1 status, which had been determined previously. Group 1 showed no abnormality in either cyclin D1 or p27Kip1 expression. Group 2 showed aberrant expression of one of the two proteins, whereas group 3 showed concurrent abnormalities in both proteins. Results indicated that overall survival was greatest in group 1, followed by a significant decrease in group 2 and a more precipitous decrease in group 3. In conclusion, cyclin D1 overexpression is an early event in gallbladder carcinogenesis and independently predicts decreased survival for patients with GBC.     

Cyclin D1 overexpression is an indicator of poor prognosis in resectable non-small cell lung cancer.

Cyclin D1 is one of the G1 cyclins that control cell cycle progression by allowing G1 to S transition. Overexpression of cyclin D1 has been postulated to play an important role in the development of human cancers. We have investigated the correlation between cyclin D1 overexpression and known clinicopathological factors and also its prognostic implication on resected non-small-cell lung cancer (NSCLC) patients. Formalin-fixed and paraffin-embedded tumour tissues resected from 69 NSCLC patients between stages I and IIIa were immunohistochemically examined to detect altered cyclin D1 expression. Twenty-four cases (34.8%) revealed positive immunoreactivity for cyclin D1. Cyclin D1 overexpression is significantly higher in patients with lymph node metastasis (50.0% vs 14.4%, P = 0.002) and with advanced pathological stages (I, 10%; II, 53.8%; IIIa, 41.7%, P = 0.048; stage I vs II, IIIa, P = 0.006). Twenty-four patients with cyclin D1-positive immunoreactivity revealed a significantly shorter overall survival than the patients with negativity (24.0 +/- 3.9 months vs 50.1 +/- 6.4 months, P = 0.0299). Among 33 patients between stages I and II, nine patients with cyclin D1-positive immunoreactivity had a much shorter overall survival (29.7 +/- 6.1 months vs 74.6 +/- 8.6 months, P = 0.0066). These results suggest that cyclin D1 overexpression is involved in tumorigenesis of NSCLCs from early stage and could be a predictive molecular marker for poor prognosis in resectable NSCLC patients, which may help us to choose proper therapeutic modalities after resection of the tumor.     

Aldehyde dehydrogenase-1 is a specific marker for stem cells in human lung adenocarcinoma

To investigate whether aldehyde dehydrogenase-1 (ALDH-1) in human lung cancer can be used as a sorting marker for stem cells in targeted therapies against human lung cancer. Spheres were induced by incubating cancer cells in a serum-free medium and formed with epidermal growth factor and fibroblast growth factor-10 (FGF10). Spheroid cells were combined with flow cytometry using the Aldefluor reagent to separate the SSCloALDEbr (ALDH-1-positive) cells. Cancer stem cells (CSCs) were characterized by their proliferation, colony formation, and tumorigenesis in nude mice and using phenotypic analysis. Float-growing spheres (“pulmospheres”) were developed after SPC-A1 cells were cultured in a serum-free medium. The resultant sphere-forming cells included ALDH-1-positive cells as high as 15.13%. ALDH-1-positive CSCs have high proliferative ability, high cloning efficiency, and strong tumorigenicity. The rate of SSC^loALDE^br cell colony formation was 1.3–5.6%, whereas that of ALDE⁻ cell colony formation was only 0–1.2% (P < 0.05). A cell count of only 1 × 10³ SSC^loALDE^br cells was necessary to form tumors, whereas at least l × 10⁵ ALDE⁻ cells formed tumors. The same number of SSC^loALDE^br cells also formed larger tumors in a short latency period of tumor formation. The expression rates of CD133 in the SSC^loALDE^br and ALDE⁻ cells were 16.31% (16.31 × 10⁴/10⁶) and 2.56% (2.56 × 10⁴/10⁶), respectively (P < 0.01). Moreover, the expression rates of ABCG2 in SSC^loALDE^br and ALDE⁻ cells were 17.62% (17.62 × 10⁴/10⁶) and 3.45% (3.45 × 10⁴/10⁶), respectively (P < 0.01). Human lung adenocarcinoma bears CSCs, and ALDH-1 can act as a specific marker for human lung CSCs.