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Clinical Cancer Research Vol. 6, 11-16, January 2000
© 2000 American Association for Cancer Research

Advances in Brief

Cyclin E Expression, a Potential Prognostic Marker for Non-Small Cell Lung Cancers

Takayuki Mishina1, Hirotoshi Dosaka-Akita1, 2, Fumihiro Hommura, Motoi Nishi, Tetsuya Kojima, Shigeaki Ogura, Michio Shimizu, Hiroyuki Katoh and Yoshikazu Kawakami

First Department of Medicine [T. M., H. D-A., F. H., T. K., S. O., Y. K.] and Second Department of Surgery [H. K.], Hokkaido University School of Medicine, Department of Surgical Pathology, Hokkaido University Medical Hospital [M. S.], and Department of Public Health, Sapporo Medical University School of Medicine [M. N.], Sapporo 060-8638, Japan


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Cyclin E is a G1 cyclin that has been shown to be one of the key regulators of the G1-S transition and could consequently be a deregulated molecule in tumors. In the present study, we have characterized cyclin E expression by immunohistochemistry in 217 resected non-small cell lung cancers (NSCLCs) and found large variations in cyclin E expression among tumors. High-level cyclin E expression (a cyclin E-labeling index >=30%), observed in 115 (53%) of 217 NSCLCs, was more frequently found in tumors from smokers than from nonsmokers (P = 0.001), in squamous cell carcinomas than in nonsquamous cell carcinomas (P = 0.0002), and in pT2–4 tumors than in pT1 tumors (P = 0.04) by the {chi}2 test. Multivariate logistic regression analysis for the correlation between cyclin E expression and various characteristics showed a significant association of high-level cyclin E expression with squamous cell carcinomas (P = 0.005). Patients with tumors having high-level cyclin E expression survived a significantly shorter time than patients with tumors having low-level expression, both among the 151 patients with potentially curatively resected NSCLCs (5-year survival rates, 48 and 63%, respectively; P = 0.03) and the 103 patients with p stage I NSCLCs (5-year survival rates, 57 and 81%, respectively; P = 0.007). High-level cyclin E expression was also a significant and independent unfavorable prognostic factor in both patients with potentially curatively resected NSCLCs (P = 0.01) and in those with p stage I NSCLCs (P = 0.03) by Cox’s proportional hazards model analysis. These findings indicate that cyclin E may play a pivotal role for the biological behavior of NSCLCs, and that a high level of cyclin E expression may be a new prognostic marker for NSCLCs.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Lung cancer is one of the leading causes of cancer death throughout the world. Despite major advances in cancer treatment in the past two decades, the prognosis of patients with lung cancer has improved only minimally, and the overall 5-year survival rate remains <15% (1) . The possibility that adjuvant chemotherapy might improve the survival of patients with resected NSCLCs3 has encouraged efforts at identification of prognostic features of these tumors (2, 3, 4) . On the other hand, recent progress in the study of the molecular biology of cancer has contributed to a better understanding of its molecular pathogenesis, including that of lung cancer (5) . Under such circumstances, it may be possible to identify patients with a good or poor prognosis using molecular biological alterations as clinical biomarkers, including alterations of cell cycle regulators.

Altered regulation of the cell cycle is a hallmark of human cancers (6 , 7) . The cell cycle is governed by cdks, the activity of which is regulated by the binding of positive effectors, the cyclins (8 , 9) , and by negative regulators, the cdk inhibitors (10 , 11) . The cdks integrate mitogenic and growth-inhibitory signals and coordinate cell cycle transitions (8 , 9) . Progression through the G1 phase of the cell cycle is dependent upon the activity of G1 cyclins, which include the D-type cyclins and cyclin E. The D-type cyclins reach maximal levels of expression and form functional kinase complexes with cdk4 or cdk6 during the mid-G1 phase (12, 13, 14, 15, 16, 17) , whereas cyclin E is expressed and associated with cdk2 in an active complex near the G1-S boundary (18 , 19) . High-level cyclin E expression seems to be specific for tumor cells, to represent a true tumor-associated abnormality, and to be a potential prognostic marker of breast cancer (20, 21, 22) . However, little is known about cyclin E in lung cancer, and there are no studies where the potential prognostic importance of cyclin E expression has been analyzed in NSCLCs.

We have reported previously alterations of regulator molecules of the G1-S transition, including p53, RB, and p16INK4A, and their biological and clinical importance in resected NSCLCs (23, 24, 25, 26) . Moreover, we have demonstrated recently by immunohistochemistry that cyclin D1 is expressed in a subset of resected NSCLCs, and that patients with NSCLCs expressing cyclin D1 survive longer than those with NSCLCs not expressing cyclin D1 (27) .

The present study underlines the considerable heterogeneity in cyclin E expression of individual NSCLCs, a heterogeneity likely to be reflected in the biological behavior of the tumors. We herein show that staining for cyclin E will reliably predict the prognosis of patients with NSCLCs and thereby help select patents who may benefit from adjuvant therapy.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Tumor Specimens and Survival Data.
Primary tumor specimens from 217 NSCLCs were consecutively obtained by surgery from the Hokkaido University Medical Hospital during 1976 and 1994. The patients with NSCLCs consisted of 147 men and 70 women (average age at diagnosis, 63.3 years). The histological classification of the tumor specimens was based on WHO criteria (28) , and the specimens included 92 squamous cell carcinomas, 107 adenocarcinomas, 9 large cell carcinomas, and 9 adenosquamous cell carcinomas. They represented 119 stage I, 18 stage II, 72 stage IIIa, 1 stage IIIb, and 7 stage IV tumors. The postsurgical pathological Tumor-Node-Metastasis stage was determined according to the guidelines of the American Joint Committee on Cancer (29) . A total of 176 tumors were potentially curatively resected. Of the 176 patients, survival was analyzed for the 151 patients who met the following criteria: (a) survived for >3 months after surgery; (b) did not die of causes other than lung cancer within 5 years after surgery; and (c) were followed for >3 years after surgery (for patients who remained alive). Fourteen patients who did not meet the above criteria (six died within 3 months after surgery, and eight died of causes other than lung cancer within 5 years) were excluded from the survival analysis. Eleven patients for whom no survival records after surgery were obtained were also excluded from the survival analysis. One hundred ten patients received combination chemotherapy as postsurgical treatment. Radiation therapy was not performed before or after surgery for any patients. Because all of the patients were coded, they could not be individually identified.

Immunohistochemistry for Cyclin E.
Cyclin E expression was analyzed by immunohistochemistry. The labeled streptavidin-biotin method was used on 4-µm sections of formalin fixed, paraffin-embedded tissues after deparaffinization. Briefly, deparaffinized tissue sections were treated with microwaves in 10 mM citrate buffer (pH 6.0) for 10 min three times to retrieve the antigenicity. The sections were then immersed in methanol containing 1.5% hydrogen peroxide for 20 min to block the endogenous peroxidase activity and were incubated with normal rabbit serum to block the nonspecific antibody binding sites. The sections were consecutively reacted with a mouse monoclonal antihuman cyclin E antibody, HE12 (Refs. 30 and 31 ; PharMingen, San Diego, CA) at the dilution of 1:200 or with control mouse isotype-specific immunoglobulin at 4°C overnight. Immunostaining was performed by the biotin-streptavidin immunoperoxidase method with 3,3'-diaminobenzidine as a chromogen (SAB-PO kit; Nichirei, Tokyo, Japan). Methyl green was used for counterstain. A colon cancer specimen with cyclin E expression (courteously provided by Dr. Wataru Yasui of the First Department of Pathology, Hiroshima University School of Medicine, Hiroshima, Japan) was used as a positive control. Nuclear staining of tumor cells with monoclonal antibody HE12 was blocked by preincubation of antibody with bacterially expressed glutathione S-transferase-cyclin E but not with glutathione S-transferase, as was reported previously (31) .

The cyclin E labeling index (%) was defined as the percentage of tumor cells displaying nuclear immunoreactivity and was calculated by counting cyclin E-nuclear stained tumor cells in 1000 tumor cells in each section. A single representative tissue section from each tumor was surveyed microscopically at x100 for at least two or three areas, with highest cyclin E intensity of positive tumor cells. Cell counts were performed at x400 in at least five fields in these areas, using a Videomicrometer (Model VM-30; Olympus, Tokyo, Japan) equipped with a light microscope. The cyclin E labeling index was reliably and reproducibly obtained using this Videomicrometer system.

Statistical Analysis.
The associations between cyclin E expression and categorical variables were analyzed by the {chi}2 test or Fisher’s exact test as appropriate. The associations between cyclin E expression and age were analyzed by Student’s t test. The survival curves were estimated using the Kaplan-Meier method, and differences in survival distributions were evaluated by the generalized Wilcoxon test. Cox’s proportional hazards modeling of factors potentially related to survival was performed to identify which factors might have a significant influence on survival. The significance level chosen was P < 0.05, and all tests were two-sided.


   Results
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Typical immunohistochemistry patterns for cyclin E in NSCLCs are shown in Fig. 1Citation . Cyclin E expression was consistently found in the nuclei of tumor cells in the present study. No nuclear staining was observed in any concomitant interstitial cells or lymphoid cells of tumors, or in normal ciliated bronchial epithelial cells, peribronchial gland cells, or alveolar pneumocytes. Occasional cytoplasmic staining was found in endothelial cells of tumor-associated blood vessels, as has been reported previously (31) .



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  		Fig. 1. Immunohistochemical staining patterns for cyclin E in NSCLCs. A, a squamous cell carcinoma with a cyclin E labeling index of 87%; B, an adenocarcinoma with a cyclin E labeling index of 83%; C, an adenocarcinoma with a cyclin E labeling index of 0%. Bar, 20 µm.

 
To define an appropriate cutoff level for cyclin E labeling indices in the subsequent statistical analysis, we looked at their distribution among NSCLCs. Fig. 2Citation shows a histogram for the distribution of cyclin E labeling indices in the 217 NSCLCs studied in the present study. The cyclin E labeling indices were considerably skewed and consisted of two populations with a cutoff level of 30%: one population with low-level cyclin E expression showing small variations; and the other population with high-level expression showing large variations. The tumors were accordingly divided into a group with cyclin E labeling indices <30%, and the other group with cyclin E labeling indices >=30%, subsequently said to have "low" or "high" cyclin E expression, respectively.



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  		Fig. 2. Distribution of cyclin E labeling indices in NSCLCs. A histogram for the distribution of cyclin E labeling indices in 217 NSCLCs studied in the present study is shown. Arrow, proposed cutoff level at the cyclin E labeling index of 30%.

 
High cyclin E expression was observed in 115 (53%) of the 217 NSCLCs. Low cyclin E expression was observed in 102 tumors (47%; Table 1Citation ). High cyclin E expression was significantly more prevalently found in tumors from men than in those from women (P = 0.005), in tumors from smokers compared with nonsmokers (P = 0.001), and in squamous cell carcinomas compared with nonsquamous cell carcinomas (P = 0.0002) by the {chi}2 test. It tended to be found more frequent in moderately and poorly differentiated tumors than in well-differentiated tumors (P = 0.07). High cyclin E expression was more frequently found in pT2–4 tumors compared with pT1 tumors (P = 0.04) but was not associated with pN and pM classifications and p stage. Multivariate logistic regression analysis for the correlation between cyclin E expression and various characteristics showed a significant association of high-level cyclin E expression with squamous cell carcinomas (P = 0.005; Table 2Citation ).


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  		Table 1 Relationship between cyclin E expression and clinical and clinicopathological characteristics in 217 surgically resected NSCLCs

 

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  		Table 2 Multivariate logistic regression analysis for the correlation between cyclin E expression and clinical and clinicopathological characteristics

 
We next analyzed the relationship between high or low cyclin E expression and patient survival (Fig. 3)Citation . In 151 patients with potentially curatively resected NSCLCs, patients with tumors having high cyclin E expression survived a significantly shorter time than patients with tumors having low expression (5-year survival rates, 48 and 63%, respectively, by the Kaplan-Meier method; P = 0.03 by the generalized Wilcoxon test; Fig. 3A)Citation . Even in the 103 patients with p stage I NSCLCs, patients with tumors having high cyclin E expression survived a significantly shorter time than patients with tumors having low expression (5-year survival rates, 57 and 81%, respectively, by the Kaplan-Meier method; P = 0.007 by the generalized Wilcoxon test; Fig. 3B)Citation .



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  		Fig. 3. Kaplan-Meier survival curves of patients with NSCLCs. Survival curves of potentially curatively resected patients (A) and of patients with p stage I tumors (B) are stratified by the cyclin E labeling index (LI). cyclin E LI <30%, low cyclin E expression; cyclin E LI >=30%, high cyclin E expression.

 
The importance of cyclin E as a prognostic factor was next analyzed by the Cox’s proportional hazards model analysis in patients with potentially curatively resected NSCLCs (Table 3)Citation . In univariate analysis of potential prognostic factors, high cyclin E expression as well as advanced pT classification, pN classification, and p stage were significant unfavorable prognostic factors (Table 3A)Citation . In multivariate analysis of prognostic factors, high cyclin E expression was a significant and independent unfavorable prognostic factor (P = 0.01), as were advanced pT classification, pN classification, and p stage (Table 3B)Citation . In patients with p stage I NSCLCs, high cyclin E expression was also a significant and independent unfavorable prognostic factor (P = 0.03) by Cox’s proportional hazards model analysis (Table 4)Citation .


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  		Table 3 Cox’s proportional hazards model analysis of prognostic factors in patients with potentially curatively resected NSCLCs

 

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  		Table 4 Cox’s proportional hazards model analysis of prognostic factors in patients with p stage I NSCLCs

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
The present study demonstrated large variations in cyclin E expression among surgically resected NSCLCs. This is, to our knowledge, the first study to show the prognostic importance of cyclin E expression in NSCLCs. High cyclin E expression was a significant and independent unfavorable prognostic factor in patients with p stage I NSCLCs as well as potentially curatively resected NSCLCs, all of which were resected at a single institute and had observation periods after surgery long enough for survival analysis.

Our observation that there was scant nuclear staining with an anti-cyclin E antibody in normal cells, while such staining was easily detected in tumor cells, indicated that the elevated staining index of cyclin E was specific for tumor cells and represented a true tumor-associated abnormality (31) . In vitro studies using carcinogen-induced transformation of immortalized human bronchial epithelial cells suggest that cyclin E plays a key role in the transformation of bronchial epithelial cells (32) . Lonardo et al. (33) have reported recently that cyclin E is frequently expressed in bronchial preneoplasia and precedes squamous cell carcinoma development, suggesting that cyclin E expression may be an important part of the multistep process in the development of NSCLCs, especially of squamous cell carcinomas. In fact, in the present study, high cyclin E expression was found more frequently in squamous cell carcinomas than in nonsquamous cell carcinomas. The association between cyclin E expression and gender or tobacco smoking by the {chi}2 test may have been attributable to the fact that cyclin E expression was found frequently in squamous cell carcinomas, which were prevalently seen in men with smoking habits. Alternatively, the smoking habit, which was more frequently found in men than in women in this cohort (data not shown), might cause high cyclin E expression via still unknown mechanisms, because heavier smoking (more pack-years of smoking) was dose responsively associated with an increased frequency of high cyclin E expression (Table 1)Citation . Consequently, high cyclin E expression could play a role in the development of NSCLCs, especially of squamous cell carcinomas.

Several lines of evidence indicate that cyclin E overexpression may be important in the development of breast cancer (20 , 31 , 34 , 35) . Normal cell cycle regulation by cyclin E has also been shown to be defective in breast cancer cells, where cyclin E is expressed constitutively in an active complex with cdk2 throughout the cell cycle (36) . In particular, cyclin E overexpression has been demonstrated in association with advanced tumor stage, increasing grade, and unfavorable prognosis in breast cancer (20, 21, 22) . These findings in breast cancer are consistent with the results of the present study of NSCLCs. Furthermore, cyclin E is also altered in other types of solid tumors as well as leukemias and lymphomas (37, 38, 39, 40) . Collectively, these observations suggest that the high cyclin E expression in NSCLCs found in this study are not a mere consequence of cell proliferation but represent a significant difference between normal and cancer cells, and that cyclin E plays a pivotal role for the biological behavior of NSCLCs and, as such, represents a potential new prognostic marker for NSCLCs.

High cyclin E expression was a unfavorable prognostic factor in patients with NSCLCs in this study, whereas patients having NSCLCs expressing cyclin D1 survived longer than those having NSCLCs not expressing cyclin D1 in another cohort of our group (27) . Both cyclin E and cyclin D1 are involved in the regulation of the G1-S transition of the cell cycle (8 , 9) . However, high expression of these proteins can cause different molecular and cellular biological phenotypes of cancer cells. Cyclin E can induce chromosome instability (41) , which is involved in the development and progression of tumors, and cyclin D1 plays a role in the control of apoptosis (42) and growth suppression (43) . Such different and multifunctional properties of these cyclins may contribute to their different effects on clinical outcome of NSCLC patients. However, cyclin E and cyclin D1 expression in relation to proliferative activity and prognostic impact of these cyclins remain to be determined in a single cohort of NSCLCs.

In summary, we have demonstrated the considerable heterogeneity in cyclin E expression of individual NSCLCs, a heterogeneity likely to be reflected in the biological behavior of the tumors, and then identified cyclin E as a potential new prognostic factor of NSCLCs. Cyclin E expression may have great value in identifying NSCLC patients at high risk of early disease recurrence after surgery and, thus, in selecting patients who will benefit from intensive adjuvant therapy.


   ACKNOWLEDGMENTS
 
We thank Dr. Wataru Yasui of the First Department of Pathology, Hiroshima University School of Medicine, Hiroshima, Japan, for providing a colon cancer specimen with cyclin E expression as a positive control.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 These two authors contributed equally to this work. Back

2 To whom requests for reprints should be addressed, at First Department of Medicine, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo, 060-8638, Japan. Phone: 81-11-716-1161; Fax: 81-11-706-7899; E-mail: hdakita{at}med.hokudai.ac.jp Back

3 The abbreviations used are: NSCLC, non-small cell lung cancer; cdk, cyclin-dependent kinase; CI, confidence interval. Back

Received 7/21/99; revised 10/17/99; accepted 10/20/99.


   REFERENCES
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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T. Kato, S. Hayama, T. Yamabuki, N. Ishikawa, M. Miyamoto, T. Ito, E. Tsuchiya, S. Kondo, Y. Nakamura, and Y. Daigo
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Clin. Cancer Res., January 15, 2007; 13(2): 434 - 442.
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C-Q Zhu, W Shih, C-H Ling, and M-S Tsao
Immunohistochemical markers of prognosis in non-small cell lung cancer: a review and proposal for a multiphase approach to marker evaluation.
J. Clin. Pathol., August 1, 2006; 59(8): 790 - 800.
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S. Singhal, A. Vachani, D. Antin-Ozerkis, L. R. Kaiser, and S. M. Albelda
Prognostic Implications of Cell Cycle, Apoptosis, and Angiogenesis Biomarkers in Non-Small Cell Lung Cancer: A Review
Clin. Cancer Res., June 1, 2005; 11(11): 3974 - 3986.
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S.-i. Fukumoto, N. Yamauchi, H. Moriguchi, Y. Hippo, A. Watanabe, J. Shibahara, H. Taniguchi, S. Ishikawa, H. Ito, S. Yamamoto, et al.
Overexpression of the Aldo-Keto Reductase Family Protein AKR1B10 Is Highly Correlated with Smokers' Non-Small Cell Lung Carcinomas
Clin. Cancer Res., March 1, 2005; 11(5): 1776 - 1785.
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J. Brzezinski, A. Migodzinski, A. Toczek, J. Tazbir, and M. Dedecjus
Patterns of Cyclin E, Retinoblastoma Protein, and p21Cip1/WAF1 Immunostaining in the Oncogenesis of Papillary Thyroid Carcinoma
Clin. Cancer Res., February 1, 2005; 11(3): 1037 - 1043.
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H. Dosaka-Akita, E. Miyoshi, O. Suzuki, T. Itoh, H. Katoh, and N. Taniguchi
Expression of N-Acetylglucosaminyltransferase V Is Associated with Prognosis and Histology in Non-Small Cell Lung Cancers
Clin. Cancer Res., March 1, 2004; 10(5): 1773 - 1779.
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J. Farley, L. M. Smith, K. M. Darcy, E. Sobel, D. O'Connor, B. Henderson, L. E. Morrison, and M. J. Birrer
Cyclin E Expression Is a Significant Predictor of Survival in Advanced, Suboptimally Debulked Ovarian Epithelial Cancers: A Gynecologic Oncology Group Study
Cancer Res., March 15, 2003; 63(6): 1235 - 1241.
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M. D. Brundage, D. Davies, and W. J. Mackillop
Prognostic Factors in Non-small Cell Lung Cancer* : A Decade of Progress
Chest, September 1, 2002; 122(3): 1037 - 1057.
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H. Dosaka-Akita, F. Hommura, T. Mishina, S. Ogura, M. Shimizu, H. Katoh, and Y. Kawakami
A Risk-Stratification Model of Non-Small Cell Lung Cancers Using Cyclin E, Ki-67, and ras p21: Different Roles of G1 Cyclins in Cell Proliferation and Prognosis
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C. Müller-Tidow, R. Metzger, K. Kügler, S. Diederichs, G. Idos, M. Thomas, B. Dockhorn-Dworniczak, P. M. Schneider, H. P. Koeffler, W. E. Berdel, et al.
Cyclin E is the Only Cyclin-dependent Kinase 2-associated Cyclin that Predicts Metastasis and Survival in Early Stage Non-Small Cell Lung Cancer
Cancer Res., January 1, 2001; 61(2): 647 - 653.
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Y. Dong, L. Sui, Y. Tai, K. Sugimoto, T. Hirao, and M. Tokuda
Prognostic Significance of Cyclin E Overexpression in Laryngeal Squamous Cell Carcinomas
Clin. Cancer Res., November 1, 2000; 6(11): 4253 - 4258.
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F. Hommura, H. Dosaka-Akita, T. Mishina, M. Nishi, T. Kojima, H. Hiroumi, S. Ogura, M. Shimizu, H. Katoh, and Y. Kawakami
Prognostic Significance of p27KIP1 Protein and Ki-67 Growth Fraction in Non-small Cell Lung Cancers
Clin. Cancer Res., October 1, 2000; 6(10): 4073 - 4081.
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