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© 2003 American Society for Clinical Oncology
Cyclin D1 Expression in the Field of Exposure: Another Piece in the Molecular Auerbach PuzzleThe University of Texas M.D. Anderson Cancer Center, Houston, TX FORTY-FIVE YEARS ago, Oscar Auerbach performed a historic study of the lungs of 117 male smokers who had died, with or without lung cancer, by obtaining step histologic sections of the entire tracheobronchial tree.1 He and his colleagues demonstrated widespread evidence of focal hyperplasia, metaplasia, dysplasia, and carcinoma-in-situ, with the number of such lesions increasing with the amount the patient had smoked. It was clear that chronic exposure to cigarette smoke led to malignant change in the bronchial epithelial cells throughout the tracheobronchial tree, creating a field of changes that varied in histologic appearance and malignant potential from minimally abnormal to more advanced disease. The conclusion drawn from this study was that lung cancer develops stepwise from normal epithelial cells, advancing through stages that are characterized by progressive epithelial disorganization, nuclear atypia, and invasion. This study was the first description of a field effect caused by chronic exposure to cigarette smoke, and it formed the basis of the multistep hypothesis of lung tumorigenesis.
Since these landmark studies, research efforts have moved from the histologic to the molecular arena, a shift that has led to the discovery of genetic and biochemical alterations in the bronchial epithelium. One of the best-characterized changes in non–small-cell lung cancer (NSCLC) is the overexpression of cyclin D1, a topic addressed by Ratschiller et al2 in this issue of the Journal of Clinical Oncology. Cyclins are the regulatory subunits of cyclin-dependent kinases (CDKs), which must bind to cyclins to be activated.3 The D-type cyclins (D1, 2, and 3) are the rate-limiting controllers of G1 phase progression in mammalian cells (Figure 1
This cyclical rhythm of cyclin D expression is crucial to the maintenance of normal cellular proliferation. In a variety of other cancer types, including parathyroid adenoma, mantle-cell lymphoma, squamous cell carcinoma of the head and neck, esophageal cancer, breast cancer, hepatocellular carcinoma, and small-cell lung cancer, cyclin D1 is overexpressed, in some cases because of amplification of a portion of chromosome 11q13 that includes the cyclin D1 gene.3 Efforts are underway to investigate the role of cyclin D1 overexpression in cancer development. The most direct evidence in support of this hypothesis is that mice genetically programmed to overexpress cyclin D1 in breast epithelial cells develop ductal hyperproliferation and, eventually, tumor formation. Ratschiller et al2 examined the role of cyclin D1 in lung tumorigenesis, which builds on work published by this group and others providing evidence that cyclin D1 is overexpressed at early stages of lung tumorigenesis.4–8 Cyclin D1 is overexpressed at premalignant stages of other tumor types as well, including breast, head and neck, pancreatic, endometrial, and hepatocellular carcinoma.9–13 Ratschiller examined tumorous and tumor-free bronchial epithelium (six sites per patient) from patients with resectable NSCLC to measure cyclin D1 expression levels by immunohistochemical analysis and allelic preference by restriction-fragment length polymorphism analysis of a polymorphism in the 3' untranslated region of cyclin D1 RNA. They found that cyclin D1 was overexpressed frequently (58%) in tumor-free epithelium. Further, overexpression was tightly associated with the presence of allelically imbalanced gene transcripts (P = .004), supporting the authors’ previous findings in NSCLC.5 Gene amplification accounted for cyclin D1 overexpression in a small proportion of patients (5%). In 50% of patients, the six tumor-free sites differed from the tumor and among themselves with respect to cyclin D1 overexpression and allelic imbalance. However, in a strikingly high proportion of patients (42%), the tumor and six tumor-free sites demonstrated similar allelically imbalanced RNA expression and cyclin D1 protein levels. On the basis of these findings, the authors conclude that cyclin D1 overexpression is an early event in lung tumorigenesis and that NSCLC consists of two distinct types: one type that overexpresses cyclin D1 from a single allele and another type that overexpresses cyclin D1 from either allele. It would be interesting to evaluate whether these two groups differ with respect to extent of histologic change for the purpose of examining the effect of malignant progression on allelic expression. Future studies should also examine, in patients whose tumor and tumor-free sites demonstrate similar allelic expression, whether allelic exclusion reflects a clonal relationship between these sites. Supporting this possibility, related clones have been identified at distinct sites in the field of exposure in patients with squamous cell carcinoma of the head and neck.14,15 Ratschiller et al2 also found evidence that, in a small proportion of the sampled sites (5%), cyclin D1 was localized in the nucleus. Nuclear localization correlated with histologic evidence of premalignancy (P < .0001), and nuclear localization in at least one site was linked to heavy smoking (P = .02) and to shorter overall survival (P = .01). Because the presence of nuclear cyclin D1 was linked to advanced premalignant change, it would be of interest to determine whether the shorter survival was a consequence of second primary tumor development. Future studies should also address the prognostic role of nuclear cyclin D1 and whether nuclear localization contributed to the negative effect of retinoid treatment in recently completed lung cancer chemoprevention trials. This possibility is intriguing, but other factors need to be considered as well, including the synergistic interaction between retinoids and exposure to cigarette smoke, which has been shown to induce proliferation in the lung.16 On the basis of what we have learned about cyclin D1 overexpression in NSCLC, we could consider strategies to target cyclin D1 in lung cancer therapeutics. For example, new strategies might be considered to activate the ubiquitin-proteasome complex to reduce cyclin D1 levels in tumors.17 We might also use immunohistochemical analysis to detect nuclear cyclin D1 in sputum samples to examine cyclin D1 as a marker of lung cancer risk or occult malignancy. In support of this approach are findings that immunohistochemical analysis of heterogeneous nuclear ribonucleoprotein B1 can detect occult lung malignancy in sputum.18 Successful lung cancer screening approaches in large populations will require highly sensitive and specific methods to detect markers in tissues that are easily accessible, such as sputum or surrogate tissues such as blood or buccal mucosa. For example, polymerase chain reaction–based technology can be used to detect aberrant methylation of certain gene promoters in sputum, and aberrant methylation has been found in the sputum of 100% of patients with squamous cell carcinoma of the lung up to 3 years before clinical diagnosis.19 This technology can also be used to detect a variant cyclin D1 allele recently found to correlate with resistance to chemopreventive intervention and shorter progression-free survival in patients with premalignancy of the upper aerodigestive tract.20 Because molecular abnormalities accumulate in cells as they progress toward a fully transformed state, these assays might be more effective if used in combination. By identifying genetic and biochemical events in the field of exposure, we will gradually assemble the pieces of a molecular Auerbach puzzle. These events can then be examined in cellular and animal models to determine their importance in lung tumorigenesis. The Auerbach model applies to other tobacco-related malignancies, including head and neck and bladder carcinomas, and it might be considered for other tumors that arise in an epithelial field exposed to carcinogens, such as colon carcinoma. Some of the important pieces of the puzzle in NSCLC are on the table, and others are still lacking. Once these pieces are assembled, we can use them to build a lung cancer risk model for the screening of smokers and former smokers. The latter group now accounts for 50% of new lung cancer cases, underscoring the importance of continuing lung cancer risk assessment after smoking cessation. Through these efforts, we may finally make progress in reducing the mortality associated with this disease, which is still the leading cause of cancer-related death in this country.
REFERENCES 1. Auerbach O, Stout AP, Hammond EC, et al: Changes in bronchial epithelium in relation to smoking and cancer of the lung. N Engl J Med 256:97–104, 1957[Medline]
2. Ratschiller D, Heighway J, Gugger M, et al: Cyclin D1 overexpression in bronchial epithelia of patients with lung cancer is associated with smoking and predicts survival. J Clin Oncol 21:2085–2093, 2003
3. Sherr CJ: Cancer cell cycles. Science 274:1672–1676, 1996 4. Betticher DC, Thatcher N, Altermatt HJ, et al: Alternate splicing produces a novel cyclin D1 transcript. Oncogene 11:1005–1011, 1995[Medline] 5. Betticher DC, Heighway J, Hasleton PS, et al: Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. Br J Cancer 73:294–300, 1996[Medline] 6. Betticher DC, Heighway J, Thatcher N, et al: Abnormal expression of CCND1 and RB1 in resection margin epithelia of lung cancer patients. Br J Cancer 75:1761–1768, 1997[Medline]
7. Brambilla E, Gazzeri S, Moro D, et al: Alterations of Rb pathway (Rb-p16INK4-cyclin D1) in preinvasive bronchial lesions. Clin Cancer Res 5:243–250, 1999
8. Lonardo F, Rusch V, Langenfeld J, et al: Overexpression of cyclins D1 and E is frequent in bronchial preneoplasia and precedes squamous cell carcinoma development. Cancer Res 59:2470–2476, 1999
9. Biankin AV, Kench JG, Morey AL, et al: Overexpression of p21 (WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. Cancer Res 61:8830–8837, 2001 10. Ruhul QM, Latkovich P, Castellani WJ, et al: Expression of cyclin D1 in normal, metaplastic, hyperplastic endometrium and endometrioid carcinoma suggests a role in endometrial carcinogenesis. Arch Pathol Lab Med 126:459–463, 2002[Medline] 11. Choi YL, Park SH, Jang JJ, et al: Expression of the G1-modulators in hepatitis B virus-related hepatocellular carcinoma and dysplasia nodule: Association of cyclin D1 and p53 proteins with the progression of hepatocellular carcinoma. J Korean Med Sci 16:424–432, 2001[Medline] 12. Rousseau A, Lim MS, Lin Z, et al: Frequent cyclin D1 gene amplification and protein overexpression in oral epithelial dysplasias. Oral Oncol 37:268–275, 2001[CrossRef][Medline] 13. Gillett CE, Lee AH, Millis RR, et al: Cyclin D1 and associated proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia. J Pathol 184:396–400, 1998[CrossRef][Medline] 14. Jang SJ, Chiba I, Hirai A, et al: Multiple oral squamous epithelial lesions: Are they genetically related? Oncogene 20:2235–2242, 2001[CrossRef][Medline]
15. Califano J, Westra WH, Meininger G, et al: Genetic progression and clonal relationship of recurrent premalignant head and neck lesions. Clin Cancer Res 6:347–353, 2000
16. Wang XD, Liu C, Bronson RT, et al: Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke. J Natl Cancer Inst 91:60–66, 1999 17. Dragnev KH, Freemantle SJ, Spinella MJ, et al: Cyclin proteolysis as a retinoid cancer prevention mechanism. Ann N Y Acad Sci 952:13–22, 2001[Medline]
18. Sueoka E, Sueoka N, Goto Y, et al: Heterogeneous nuclear ribonucleoprotein B1 as early cancer biomarker for occult cancer of human lungs and bronchial dysplasia. Cancer Res 61:1896–1902, 2001
19. Palmisano WA, Divine KK, Saccomanno G, et al: Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res 60:5954–5958, 2000
20. Izzo JG, Papadimitrakopoulou VA, Liu DD, et al: Cyclin D1 genotype, response to biochemoprevention, and progression rate to upper aerodigestive tract cancer. J Natl Cancer Inst 95:198–205, 2003
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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