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Overexpression of Cyclin B1 in Early-Stage Non-Small Cell Lung Cancer and Its Clinical Implication¹

Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

	ABSTRACT

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Cyclin B1 is a key molecule for G₂-M-phase transition during the cell cycle and is overexpressed in various tumor types. However, the expression status of cyclin B1 in lung cancer and its clinical significance remain unknown. We used immunohistochemistry studies to examine the expression of cyclin B1 in 77 non-small cell lung cancer specimens from patients with histological stage I disease. All of the patients underwent curative surgical treatment. The median length of follow-up care is 8.2 years. High-level cyclin B1 expression (a cyclin B1 labeling index 15%) was observed in 17 of the 77 (22%) tumors. Patients whose tumors expressed a high level of cyclin B1 had a significantly shorter survival time than patients whose tumors expressed a low level of cyclin B1 (P = 0.02, log-rank test). Interestingly, overexpression of cyclin B1 was more frequently observed in tumors with squamous cell histology than in tumors with other histological cell types (P = 0.01, Fisher’s exact test). A subgroup analysis revealed that cyclin B1 overexpression seems to be an adverse prognostic factor only in patients with squamous cell carcinoma (SCC) of the lung (P = 0.02, log-rank test). Our data indicate that cyclin B1 may be dysregulated in non-small cell lung cancer, particularly in the SCC subtype, and that a high level of cyclin B1 expression may be a prognostic marker for patients with early-stage SCC of the lung.

	Introduction

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Lung cancer is a major cause of mortality worldwide. In the United States alone, it was estimated that 164,100 new cases of lung cancer would be diagnosed in 2000, with an estimated 156,900 deaths (1) . NSCLC³ represents about 80% of all lung cancers, and its dismal survival rate has not improved significantly in the past two decades. Even patients with pathological stage I NSCLC have only a 60% survival rate at 5 years (2) . To further improve the survival rate in this group of patients, their prognostic classification based on tumor biology will be crucial. Such classification might help clinicians to make the right management decisions for each subset of patients.

Altered regulation of the cell cycle is a hallmark of human cancers (3) . Cell cycle progression is governed by a series of cyclins and cdks. Individual cyclins act at different phases of the cell cycle by binding and activating corresponding cdks. Of the various cyclin/cdk complexes involved in cell cycle regulation, cyclin D1/cdk4/6 and cyclin B1/Cdc2 are of particular interest because the former directs G₁-S-phase transition and the latter controls G₂-M-phase checkpoint surveillance, which are in turn essential for DNA synthesis and cell proliferation. Dysregulated expression of these cyclins, cdks, or both may lead to uncontrolled cell growth and malignant transformation. Overexpression and/or amplification of cyclin D1 has been reported in a large variety of human cancers, including those of the esophagus, head and neck, lung, liver, and breast (3) and is reported to be of prognostic importance in patients with most of these tumor types (4, 5, 6) . Overexpression of cyclin B1 has been reported more recently in breast, colon, prostate, oral, and esophageal carcinomas (7, 8, 9, 10, 11) . Its prognostic value has been suggested in patients with SCC of the esophagus (11) . However, little is known about cyclin B1 expression status in lung cancer and its potential clinical application in this tumor type.

To determine whether cyclin B1 expression is dysregulated in early-stage NSCLC and whether it can be used as a prognostic marker in patients with NSCLC, we examined immunohistochemically the expression pattern of cyclin B1 in 77 patients with pathological stage I NSCLC. We found that cyclin B1 was overexpressed in about 20% of the tumors analyzed (34% of SCC and 12% of non-SCC tumors) and that this overexpression is an adverse prognostic factor of survival time for patients with stage I NSCLC.

	Materials and Methods

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Study Population.
The primary NSCLC specimens were archived tissue samples of surgically resected pathological stage I tumors from 77 patients treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX). All patients were treated by surgery alone and received a median of 8.2 years of follow-up care after surgical treatment. Surgical specimens were collected between 1975 and 1990. Survival data were available for all patients and with a minimum length of follow-up care of 5 years. The study population consisted of 54 men and 23 women. The mean age of patients was 65 years. Histological subtypes included 35 SCCs, 33 adenocarcinomas, 3 bronchoalveolar carcinomas, 3 large cell carcinomas, 1 adenosquamous carcinoma, and 2 unclassified tumors (Table 1) .

The cyclin B1 labeling index was defined as the percentage of tumor cells displaying cytoplasmic or nuclear immunoreactivity and calculated by counting the number of cyclin B1-stained tumor cells among at least 1000 tumor cells for each section. Similarly, the Ki-67 proliferative index was defined as the percentage of nuclear-stained cells among 1000 or more tumor cells. Representative areas of each tissue section were selected, and cells were counted in at least four fields (at x400) in these areas. All slides were scored concomitantly by a pathologist (S. J. J.) and another investigator (J-C. S.).

Statistical Analysis.
Survival curves were estimated by the Kaplan-Meier method, and the resulting curves were compared using the log-rank test. Fisher’s exact test and the ² test were used to analyze the association between two categorical variables. P < 0.05 was considered to be statistically significant. Immunohistochemical analysis was performed in a blinded manner with respect to the clinical information of the subjects. The Pearson correlation coefficient was used to test the strength of association between continuous variables (i.e., cyclin B1 and Ki-67).

	Results

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In normal ciliated bronchial epithelial cells, peribronchial gland cells, or alveolar pneumocytes, cyclin B1 expression was not detectable. Interstitial or lymphoid cells of tumor areas were occasionally immunostained. In tumor cells that stained positively for cyclin B1, the immunostaining was detected predominantly in the cytoplasm (Fig. 1 , a–c), although in a few cases, nuclear staining was also observed. In the positive control tissues (tonsil), the normal stratified squamous epithelium displayed cyclin B1-positive cells in the basal and parabasal layers. In the adjacent lymph nodes, cyclin B1-positive cells were localized predominantly in the germinal centers. Positive Ki-67 immunostaining was restricted to the cell nuclei (Fig. 1 , d–f). For Ki-67, as well as for cyclin B1, the immunohistochemical staining showed a wide heterogeneity from rare scattered cells to a homogeneous pattern for the vast majority of cells examined, suggesting that phenotypic heterogeneity is a major feature in NSCLC (Fig. 1 ). If 15% of the cells were positive for cyclin B1, the case was considered to have cyclin B1 overexpression. For Ki-67 staining, cases with 25% positive cells were considered to have high expression of Ki-67 based on previous reports (12, 13, 14) . As shown in Fig. 2 , a weak but statistically significant correlation (correlation coefficient = 0.30; P = 0.009) was found between cyclin B1 index and Ki-67 score.

View larger version (208K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Immunohistochemical staining patterns of cyclin B1 and Ki-67 in NSCLC. a, an adenocarcinoma with most cancer cells expressing cyclin B1 in the cytoplasm. b, a squamous cell carcinoma with most carcinoma cells positive for cyclin B1. c, an adenocarcinoma with rare scattered cells expressing cyclin B1 (original magnification, x400). d, an adenocarcinoma showing a strong positive reaction in the nuclei of carcinoma cells. e, a squamous cell carcinoma with most carcinoma cells positive for Ki-67. f, a bronchoalveolar form with few cells positive for Ki-67 (original magnification, x400).

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Distribution of the cyclin B1 labeling index and Ki-67 proliferative index for the study population.

We subsequently analyzed the relationship between cyclin B1 expression and length of survival. Fig. 3A shows a comparison of the Kaplan-Meier survival curves between patients whose tumors expressed a high level of cyclin B1 and those whose tumors had low cyclin B1 expression. Patients with tumors that overexpressed cyclin B1 had significantly shorter survival times than patients with tumors that displayed low levels of cyclin B1 (P = 0.02, log-rank test). About 60% of the patients whose tumors had a low cyclin B1 expression were alive at 5 years compared with only 30% of the patients whose tumors had high cyclin B1 expression (Table 1) . The prognostic significance of cyclin B1 expression was further explored in terms of the major histological subtypes. Cyclin B1 overexpression was a significant adverse prognostic factor among patients with tumors of the SCC subtype (P = 0.02, log-rank test; Fig. 3B ) as opposed to patients with adenocarcinoma (Fig. 3C ). Because Ki-67 and cyclin B1 expression had a weak correlation, the prognostic significance of Ki-67 was also explored, but no statistically significant effect was observed (Fig. 3D ).

View larger version (28K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. A, survival curves of patients with stage I NSCLC according to cyclin B1 expression; B, survival curves of patients with stage I squamous cell carcinoma according to cyclin B1; C, survival curves of patients with stage I adenocarcinoma according to cyclin B1; D, survival curves of patients with stage I NSCLC according to Ki-67.

	Discussion

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In the present study, we demonstrated that cyclin B1 is overexpressed in a significant fraction of NSCLCs. Overall, 17 of the 77 (22%) tumors expressed cyclin B1 in 15% of tumor cells. Interestingly, cyclin B1 expression was different when SCC tumors were compared with non-SCC samples. High cyclin B1 expression was observed in 34% of SCC tumors but in only 12% of tumors with other histological subtypes (Table 1) . Furthermore, our data show that high cyclin B1 expression is a significant unfavorable prognostic factor in patients with stage I NSCLC. The fact that all of the patients in the study were treated at a single institute and received lengthy follow-up care after surgery makes survival analysis reliable. In the histological subgroup analysis, we found that the prognostic value of cyclin B1 seems to be limited to the squamous cell subtype and has no predictive value among patients with adenocarcinoma (Fig. 3 and C ). This particular observation, together with the fact that cyclin B1 expression itself differs among histological subtypes, highlights the biological differences among different subtypes of NSCLC. Different abnormalities in oncogenes and tumor suppressor genes among histological subtypes of NSCLC are well-known. Indeed, K-ras mutations are much more common in adenocarcinomas than in SCCs, whereas the p53 mutant immunophenotype is more frequent in squamous carcinomas than in adenocarcinoma (17 , 18) .

To determine whether overexpression of cyclin B1 in NSCLC simply reflects the increased cell proliferation, we analyzed Ki-67, a well-established marker of cell proliferation that is not phase specific in the cell cycle, in contiguous sections of the tumors. Consistent with previous reports, a weak correlation (0.30; P = 0.009) was found between the cyclin B1 index and Ki-67 score (9 , 10) . Although some of the previous studies have suggested that Ki-67 is a possible indicator of length of survival (12 , 19 , 20) , we failed to show any significant prognostic value for Ki-67 in our study population. The absence of prognostic value for Ki-67 remained even when survival analysis was performed using different cutoff levels published previously [i.e., 5%, 10%, or 20%; data not shown (9 , 20 , 21) ]. Nevertheless, the prognostic significance of Ki-67 in lung cancer is not yet firmly established because some studies suggest that a high Ki-67 expression level is predictive of poor survival (12 , 19 , 20) , whereas others did not demonstrate any effect (13 , 14 , 21) . Collectively, these observations suggest that high cyclin B1 expression in NSCLCs is not a mere consequence of cell proliferation, but rather an indicator of aberrant cell cycle progression at the G₂-M-phase transition in cancer cells. Cyclin B1 also seems to play a pivotal role in the biological behavior of NSCLCs, particularly in SCC, and, in doing so, represents a potential new prognostic marker as well as a therapeutic target in NSCLC.

How overexpression of cyclin B1 participates in tumor progression remains to be established. Many authors suggest that the oncogenic role of cyclins is probably related to their unscheduled expression, namely, their expression throughout the cell cycle (22 , 23) . The unscheduled expression of cyclins in tumor cells could be the result of either impaired degradation or continued synthesis during the cell cycle. Regardless of the cause, the continuous presence of cyclins may cause activation of their respective partner kinases (cdks), which remain essentially invariable throughout the cell cycle. This, in turn, might lead to unscheduled phosphorylation of a variety of proteins, thus driving the cell through the cycle and bypassing the respective checkpoints. Recent findings that p53 controls a G₂ checkpoint through down-regulation of cyclin B1 and that constitutive activation of cyclin B1 and associated cdc2 kinase can override this p53-mediated G₂-M-phase arrest support this notion (24 , 25) .

In conclusion, this study has shown, using a homogeneous population of 77 patients with stage I NSCLC, that there is overexpression of cyclin B1 in lung tumors, particularly in SCC, and that such overexpression was associated with patients’ prognosis. More comprehensive studies involving greater numbers of patients are necessary to confirm these findings.

	Acknowledgments

 
We thank Susan Cweren, Lakshmi Kakarala, Shyla Kalapurakai, Julie Izzo, and Mathilde Sibony for helpful discussions and technical assistance with immunohistochemistry.

	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 Supported in part by American Cancer Society Grant RPG-98-054 and National Cancer Institute Grant P01 CA74173 (to L. M.), Fondation de France, AP-HP and Lilly Fondation Grant (to J-C. S.), American Cancer Society-Clinical Oncology Career Development Award 96-41 (to F. R. K.), National Cancer Institute Grant U19 CA 68437 (to W. K. H.), Cancer Center Grant P30 CA 16620 (to the M. D. Anderson Cancer Center), and Tobacco Research Fund from the State of Texas (M. D. Anderson Cancer Center). W. K. H. is an American Cancer Society Clinical Research Professor.

² To whom requests for reprints should be addressed, at Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-6363; Fax: (713) 796-8655; E-mail: lmao{at}notes.mdacc.tmc.edu

³ The abbreviations used are: NSCLC, non-small cell lung cancer; SCC, squamous cell carcinoma; cdk, cyclin-dependent kinase.

Received 3/14/00. Accepted 6/ 7/00.

	REFERENCES

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 

1. Greenlee R. T., Murray T., Bolden S., Wingo P. A. Cancer statistics, 2000. CA Cancer J. Clin., 50: 27-33, 2000.
2. Williams D. E., Pairolero P. C., Davis C. S., Bernatz P. E., Payne W. S., Taylor W. F., Uhlenhopp M. A., Fontana R. S. Survival of patients surgically treated for stage I lung cancer. J. Thorac. Cardiovasc. Surg., 82: 70-76, 1981.[Abstract]
3. Sherr C. J. Cancer cell cycles. Science (Washington DC), 274: 1672-1677, 1996.[Abstract/Free Full Text]
4. Akervall J. A., Michalides R. J. A. M., Mineta H., Balm A., Borg A., Dictor M., Jin Y., Loftus B., Mertens F., Wennerberg J. P. Amplification of cyclin D1 in squamous cell carcinoma of the head and neck and the prognostic value of chromosomal abnormalities and cyclin D1 overexpression. Cancer (Phila.), 79: 380-389, 1997.[Medline]
5. McIntosh G. G., Anderson J. J., Milton I., Steward M., Parr A. H., Thomas M. D., Henry J. A., Angus B., Lennard T. W. J., Horne C. H. W. Determination of the prognostic value of cyclin D1 overexpression in breast cancer. Oncogene, 11: 885-891, 1995.[Medline]
6. Nishida N., Fukuda Y., Komeda T., Kita R., Sando T., Furukowa M., Amenomori M., Shibagaki I., Nakao K., Ikenaga M., Ishizaki K. Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma. Cancer Res., 54: 3107-3110, 1994.[Abstract/Free Full Text]
7. Kawamoto H., Koizumi H., Uchikoshi T. Expression of the G₂-M checkpoint regulators cyclin B1 and cdc2 in nonmalignant and malignant breast lesions. Am. J. Pathol., 150: 15-23, 1997.[Abstract]
8. Wang A., Yoshimi N., Ino N., Tanaka T., Mori H. Overexpression of cyclin B1 in human colorectal cancers. J. Cancer Res. Clin. Oncol., 123: 124-127, 1997.[Medline]
9. Mashal R. D., Lester S., Corless C., Richie J. P., Chandra R., Propert K. J., Dutta A. Expression of cell cycle-regulated proteins in prostate cancer. Cancer Res., 56: 4159-4163, 1996.[Abstract/Free Full Text]
10. Kushner J., Bradley G., Young B., Jordan R. C. K. Aberrant expression of cyclin A and cyclin B1 proteins in oral carcinoma. J. Oral Pathol. Med., 28: 77-81, 1999.[Medline]
11. Murakami H., Furihata M., Ohtusi Y., Ogoshi S. Determination of the prognostic significance of cyclin B1 overexpression in patients with oesophageal squamous cell carcinoma. Virchows Arch., 434: 153-158, 1999.[Medline]
12. Scagliotti V. G., Micela M., Gubetta L., Leonardo E., Cappia S., Borasio P., Pozzi E. Prognostic significance of Ki-67 labelling in resected non-small cell lung cancer. Eur. J. Cancer, 29A: 363-365, 1993.
13. Pujol J. L., Simony J., Jolimoy G., Jaffule D., Demoly P., Quantin X., Marty-Ane C., Boher J. M., Charpentier R., Michel F. B. Hypodiploidy, Ki-67 growth fraction and prognosis of surgically resected lung cancers. Br. J. Cancer, 74: 964-970, 1996.[Medline]
14. Mehdi S. A., Etzell J. E., Newman N. B., Weidner N., Kohman L. J., Graziano S. L. Prognostic significance of Ki-67 immunostaining and symptoms in resected stage I and II non-small cell lung cancer. Lung Cancer, 20: 99-108, 1998.[Medline]
15. Ohshima K., Haraoka S., Fujiki T., Yoshioka S., Suzumiya J., Kanda M., Kikuchi M. Expression of cyclin E, A and B1 in Hodgkin and Reed-Stenberg cells: not suppressed by cyclin-dependent kinase inhibitor p21 expression. Pathol. Int., 49: 506-512, 1999.[Medline]
16. Banerjee S. K., Weston A. P., Zoubine M. N., Campbell D. R., Cherian R. Expression of cdc2 and cyclin B1 in Helicobacter pylori-associated gastric MALT and MALT lymphoma. Am. J. Pathol., 156: 217-225, 2000.[Abstract/Free Full Text]
17. Rossell R., Li S., Skacel Z., Mate J. L., Maestre J., Canela M., Tolosa M., Tolosa E., Armengol P., Barnadas A., Ariza A. Prognostic impact of mutated K-ras gene in surgically resected non-small cell lung cancer patients. Oncogene, 8: 2407-2412, 1993.[Medline]
18. Kishimoto Y., Murakami Y., Shiraishi M., Hayashi K., Sekiya T. Aberrations of the p53 tumor suppressor gene in human non-small cell carcinomas of the lung. Cancer Res., 52: 4799-4804, 1992.[Abstract/Free Full Text]
19. Pence J. C., Kerns B. J. M., Dodge R., Iglehart D. Prognostic significance of the proliferation index in surgically resected non-small-cell lung cancer. Arch. Surg., 128: 1382-1390, 1993.[Abstract/Free Full Text]
20. Viberti L., Papotti M., Abbona G. C., Celano A., Filosso P. L., Bussolati G. Value of Ki-67 immunostaining in preoperative biopsies of carcinomas of the lung. Hum. Pathol., 28: 189-192, 1997.[Medline]
21. Tungekar M. F., Gatter K. C., Dunnill M. S., Mason D. Y. Ki-67 immunostaining and survival in operable lung cancer. Histopathology, 19: 545-550, 1991.[Medline]
22. Gong J., Ardelt B., Traganos F., Darzynkiewicz Z. Unscheduled expression of cyclin B1 and cyclin E in several leukemic and solid tumor cell lines. Cancer Res., 54: 4285-4288, 1994.[Abstract/Free Full Text]
23. Kakino S., Saski K., Kurose A., Ito H. Intracellular localization of cyclin B1 during the cell cycle in glioma cells. Cytometry, 24: 49-54, 1996.[Medline]
24. Innocente S. A., Abrahamson J. L. A., Gogswell J. P., Lee J. M. p53 regulates a G₂ checkpoint through cyclin B1. Proc. Natl. Acad. Sci. USA, 96: 2147-2152, 1999.[Abstract/Free Full Text]
25. Park M., Chae H. D., Yun J., Jung M., Kim Y. S., Kim S. H., Han M. H., Shin D. Y. Constitutive activation of cyclin B1-associated cdc2 kinase overrides p53-mediated G₂-M arrest. Cancer Res., 60: 542-545, 2000.[Abstract/Free Full Text]

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