Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Jun;80(8):1289–1295. doi: 10.1038/sj.bjc.6990500

Cyclin D1 expression in non-small-cell lung cancers: its association with altered p53 expression, cell proliferation and clinical outcome

T Mishina 1, H Dosaka-Akita 1, I Kinoshita 1, F Hommura 1, T Morikawa 2, H Katoh 2, Y Kawakami 1
PMCID: PMC2362358  PMID: 10376986

Abstract

Cyclin D1, like p16INK4 (p16) and retinoblastoma (RB) proteins, participates in the cell cycle control at the G1–S transition. We have previously demonstrated altered p16 and RB protein status in non-small-cell lung cancers (NSCLCs) and their potential synergistic effect with altered p53 protein on proliferative activity (Kinoshita et al (1996) Cancer Res56: 5557–5562). In the present study, cyclin D1 expression was studied by immunohistochemistry in the same cohort of 111 resected NSCLCs as in our previous study, and the amount of the cyclin D1 gene was analysed by Southern blot analysis in 29 NSCLCs. Cyclin D1 expression was analysed in relation to the status of p53, p16 and RB proteins, and proliferative activity determined by the Ki-67 index. It was also analysed in relation to survival of 77 patients with NSCLCs which were potentially curatively resected between 1990 and 1995. We found that: (1) cyclin D1 was expressed in 13 (11.7%) of 111 NSCLCs; (2) the cyclin D1 gene was neither significantly amplified nor rearranged; (3) cyclin D1 expression significantly correlated with altered p53 protein expression (P = 0.04), whereas it did not correlate with p16 and RB protein status; (4) proliferative activity tended to be higher in cyclin D1-positive (+) tumours than in cyclin D1-negative (–) tumours, although this difference was not statistically significant (P = 0.08); and (5) patients with cyclin D1+ tumours survived longer than patients with cyclin D1– tumours (5-year survival rates, 89% and 64% respectively, by the Kaplan–Meier method; P = 0.045 by the log-rank test), and cyclin D1 expression tended to be a favourable prognostic factor (P = 0.08 in univariate analysis). These findings suggest the involvement of cyclin D1 in the development and progression of NSCLCs, their proliferative activity and clinical outcome of NSCLC patients. © 1999 Cancer Research Campaign

Keywords: cyclin D1, p53, p16/RB pathway, Ki-67 index, clinical outcome, non-small-cell lung cancers

Full Text

The Full Text of this article is available as a PDF (281.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akervall J. A., Michalides R. J., Mineta H., Balm A., Borg A., Dictor M. R., 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. 1997 Jan 15;79(2):380–389. [PubMed] [Google Scholar]
  2. Bartkova J., Lukas J., Strauss M., Bartek J. Cell cycle-related variation and tissue-restricted expression of human cyclin D1 protein. J Pathol. 1994 Mar;172(3):237–245. doi: 10.1002/path.1711720303. [DOI] [PubMed] [Google Scholar]
  3. Betticher D. C., Heighway J., Hasleton P. S., Altermatt H. J., Ryder W. D., Cerny T., Thatcher N. Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. Br J Cancer. 1996 Feb;73(3):294–300. doi: 10.1038/bjc.1996.52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Betticher D. C., White G. R., Vonlanthen S., Liu X., Kappeler A., Altermatt H. J., Thatcher N., Heighway J. G1 control gene status is frequently altered in resectable non-small cell lung cancer. Int J Cancer. 1997 Oct 21;74(5):556–562. doi: 10.1002/(sici)1097-0215(19971021)74:5<556::aid-ijc14>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  5. Buckley M. F., Sweeney K. J., Hamilton J. A., Sini R. L., Manning D. L., Nicholson R. I., deFazio A., Watts C. K., Musgrove E. A., Sutherland R. L. Expression and amplification of cyclin genes in human breast cancer. Oncogene. 1993 Aug;8(8):2127–2133. [PubMed] [Google Scholar]
  6. Chen X., Bargonetti J., Prives C. p53, through p21 (WAF1/CIP1), induces cyclin D1 synthesis. Cancer Res. 1995 Oct 1;55(19):4257–4263. [PubMed] [Google Scholar]
  7. Del Sal G., Murphy M., Ruaro E., Lazarevic D., Levine A. J., Schneider C. Cyclin D1 and p21/waf1 are both involved in p53 growth suppression. Oncogene. 1996 Jan 4;12(1):177–185. [PubMed] [Google Scholar]
  8. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  9. Filmus J., Robles A. I., Shi W., Wong M. J., Colombo L. L., Conti C. J. Induction of cyclin D1 overexpression by activated ras. Oncogene. 1994 Dec;9(12):3627–3633. [PubMed] [Google Scholar]
  10. Gerdes J., Lemke H., Baisch H., Wacker H. H., Schwab U., Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984 Oct;133(4):1710–1715. [PubMed] [Google Scholar]
  11. Hannon G. J., Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994 Sep 15;371(6494):257–261. doi: 10.1038/371257a0. [DOI] [PubMed] [Google Scholar]
  12. Harada M., Dosaka-Akita H., Miyamoto H., Kuzumaki N., Kawakami Y. Prognostic significance of the expression of ras oncogene product in non-small cell lung cancer. Cancer. 1992 Jan 1;69(1):72–77. doi: 10.1002/1097-0142(19920101)69:1<72::aid-cncr2820690114>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  13. Hinds P. W., Dowdy S. F., Eaton E. N., Arnold A., Weinberg R. A. Function of a human cyclin gene as an oncogene. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):709–713. doi: 10.1073/pnas.91.2.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jiang W., Kahn S. M., Tomita N., Zhang Y. J., Lu S. H., Weinstein I. B. Amplification and expression of the human cyclin D gene in esophageal cancer. Cancer Res. 1992 May 15;52(10):2980–2983. [PubMed] [Google Scholar]
  15. Jiang W., Kahn S. M., Zhou P., Zhang Y. J., Cacace A. M., Infante A. S., Doi S., Santella R. M., Weinstein I. B. Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. Oncogene. 1993 Dec;8(12):3447–3457. [PubMed] [Google Scholar]
  16. Kinoshita I., Dosaka-Akita H., Mishina T., Akie K., Nishi M., Hiroumi H., Hommura F., Kawakami Y. Altered p16INK4 and retinoblastoma protein status in non-small cell lung cancer: potential synergistic effect with altered p53 protein on proliferative activity. Cancer Res. 1996 Dec 15;56(24):5557–5562. [PubMed] [Google Scholar]
  17. Lovec H., Sewing A., Lucibello F. C., Müller R., Möröy T. Oncogenic activity of cyclin D1 revealed through cooperation with Ha-ras: link between cell cycle control and malignant transformation. Oncogene. 1994 Jan;9(1):323–326. [PubMed] [Google Scholar]
  18. Lukas J., Müller H., Bartkova J., Spitkovsky D., Kjerulff A. A., Jansen-Dürr P., Strauss M., Bartek J. DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1. J Cell Biol. 1994 May;125(3):625–638. doi: 10.1083/jcb.125.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lukas J., Pagano M., Staskova Z., Draetta G., Bartek J. Cyclin D1 protein oscillates and is essential for cell cycle progression in human tumour cell lines. Oncogene. 1994 Mar;9(3):707–718. [PubMed] [Google Scholar]
  20. Lukas J., Parry D., Aagaard L., Mann D. J., Bartkova J., Strauss M., Peters G., Bartek J. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature. 1995 Jun 8;375(6531):503–506. doi: 10.1038/375503a0. [DOI] [PubMed] [Google Scholar]
  21. Marchetti A., Doglioni C., Barbareschi M., Buttitta F., Pellegrini S., Gaeta P., La Rocca R., Merlo G., Chella A., Angeletti C. A. Cyclin D1 and retinoblastoma susceptibility gene alterations in non-small cell lung cancer. Int J Cancer. 1998 Jan 19;75(2):187–192. doi: 10.1002/(sici)1097-0215(19980119)75:2<187::aid-ijc4>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  22. Marhin W. W., Hei Y. J., Chen S., Jiang Z., Gallie B. L., Phillips R. A., Penn L. Z. Loss of Rb and Myc activation co-operate to suppress cyclin D1 and contribute to transformation. Oncogene. 1996 Jan 4;12(1):43–52. [PubMed] [Google Scholar]
  23. Mate J. L., Ariza A., Aracil C., López D., Isamat M., Pérez-Piteira J., Navas-Palacios J. J. Cyclin D1 overexpression in non-small cell lung carcinoma: correlation with Ki67 labelling index and poor cytoplasmic differentiation. J Pathol. 1996 Dec;180(4):395–399. doi: 10.1002/(SICI)1096-9896(199612)180:4<395::AID-PATH688>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  24. Matsushime H., Roussel M. F., Ashmun R. A., Sherr C. J. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell. 1991 May 17;65(4):701–713. doi: 10.1016/0092-8674(91)90101-4. [DOI] [PubMed] [Google Scholar]
  25. McIntosh G. G., Anderson J. J., Milton I., Steward M., Parr A. H., Thomas M. D., Henry J. A., Angus B., Lennard T. W., Horne C. H. Determination of the prognostic value of cyclin D1 overexpression in breast cancer. Oncogene. 1995 Sep 7;11(5):885–891. [PubMed] [Google Scholar]
  26. Mineta H., Borg A., Dictor M., Wahlberg P., Wennerberg J. Correlation between p53 mutation and cyclin D1 amplification in had and neck squamous cell carcinoma. Oral Oncol. 1997 Jan;33(1):42–46. doi: 10.1016/s0964-1955(96)00039-5. [DOI] [PubMed] [Google Scholar]
  27. Motokura T., Bloom T., Kim H. G., Jüppner H., Ruderman J. V., Kronenberg H. M., Arnold A. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 1991 Apr 11;350(6318):512–515. doi: 10.1038/350512a0. [DOI] [PubMed] [Google Scholar]
  28. Müller H., Lukas J., Schneider A., Warthoe P., Bartek J., Eilers M., Strauss M. Cyclin D1 expression is regulated by the retinoblastoma protein. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):2945–2949. doi: 10.1073/pnas.91.8.2945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Naitoh H., Shibata J., Kawaguchi A., Kodama M., Hattori T. Overexpression and localization of cyclin D1 mRNA and antigen in esophageal cancer. Am J Pathol. 1995 May;146(5):1161–1169. [PMC free article] [PubMed] [Google Scholar]
  30. Nakagawa H., Wang T. C., Zukerberg L., Odze R., Togawa K., May G. H., Wilson J., Rustgi A. K. The targeting of the cyclin D1 oncogene by an Epstein-Barr virus promoter in transgenic mice causes dysplasia in the tongue, esophagus and forestomach. Oncogene. 1997 Mar 13;14(10):1185–1190. doi: 10.1038/sj.onc.1200937. [DOI] [PubMed] [Google Scholar]
  31. Nikaido T., Li S. F., Shiozawa T., Fujii S. Coabnormal expression of cyclin D1 and p53 protein in human uterine endometrial carcinomas. Cancer. 1996 Sep 15;78(6):1248–1253. doi: 10.1002/(SICI)1097-0142(19960915)78:6<1248::AID-CNCR12>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  32. Nishida N., Fukuda Y., Komeda T., Kita R., Sando T., Furukawa M., Amenomori M., Shibagaki I., Nakao K., Ikenaga M. Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma. Cancer Res. 1994 Jun 15;54(12):3107–3110. [PubMed] [Google Scholar]
  33. Nishio M., Koshikawa T., Yatabe Y., Kuroishi T., Suyama M., Nagatake M., Sugiura T., Ariyoshi Y., Mitsudomi T., Takahashi T. Prognostic significance of cyclin D1 and retinoblastoma expression in combination with p53 abnormalities in primary, resected non-small cell lung cancers. Clin Cancer Res. 1997 Jul;3(7):1051–1058. [PubMed] [Google Scholar]
  34. Peeper D. S., Upton T. M., Ladha M. H., Neuman E., Zalvide J., Bernards R., DeCaprio J. A., Ewen M. E. Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein. Nature. 1997 Mar 13;386(6621):177–181. doi: 10.1038/386177a0. [DOI] [PubMed] [Google Scholar]
  35. Ravitz M. J., Yan S., Dolce C., Kinniburgh A. J., Wenner C. E. Differential regulation of p27 and cyclin D1 by TGF-beta and EGF in C3H 10T1/2 mouse fibroblasts. J Cell Physiol. 1996 Sep;168(3):510–520. doi: 10.1002/(SICI)1097-4652(199609)168:3<510::AID-JCP3>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
  36. Serrano M., Hannon G. J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993 Dec 16;366(6456):704–707. doi: 10.1038/366704a0. [DOI] [PubMed] [Google Scholar]
  37. Shapiro G. I., Edwards C. D., Kobzik L., Godleski J., Richards W., Sugarbaker D. J., Rollins B. J. Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. Cancer Res. 1995 Feb 1;55(3):505–509. [PubMed] [Google Scholar]
  38. Sherr C. J. Cancer cell cycles. Science. 1996 Dec 6;274(5293):1672–1677. doi: 10.1126/science.274.5293.1672. [DOI] [PubMed] [Google Scholar]
  39. Sofer-Levi Y., Resnitzky D. Apoptosis induced by ectopic expression of cyclin D1 but not cyclin E. Oncogene. 1996 Dec 5;13(11):2431–2437. [PubMed] [Google Scholar]
  40. Spitkovsky D., Steiner P., Gopalkrishnan R. V., Eilers M., Jansen-Dürr P. The role of p53 in coordinated regulation of cyclin D1 and p21 gene expression by the adenovirus E1A and E1B oncogenes. Oncogene. 1995 Jun 15;10(12):2421–2425. [PubMed] [Google Scholar]
  41. Tanaka H., Fujii Y., Hirabayashi H., Miyoshi S., Sakaguchi M., Yoon H. E., Matsuda H. Disruption of the RB pathway and cell-proliferative activity in non-small-cell lung cancers. Int J Cancer. 1998 Apr 17;79(2):111–115. doi: 10.1002/(sici)1097-0215(19980417)79:2<111::aid-ijc2>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  42. Uchimaru K., Endo K., Fujinuma H., Zukerberg L., Arnold A., Motokura T. Oncogenic collaboration of the cyclin D1 (PRAD1, bcl-1) gene with a mutated p53 and an activated ras oncogene in neoplastic transformation. Jpn J Cancer Res. 1996 May;87(5):459–465. doi: 10.1111/j.1349-7006.1996.tb00246.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wang T. C., Cardiff R. D., Zukerberg L., Lees E., Arnold A., Schmidt E. V. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature. 1994 Jun 23;369(6482):669–671. doi: 10.1038/369669a0. [DOI] [PubMed] [Google Scholar]
  44. Weinberg R. A. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2. [DOI] [PubMed] [Google Scholar]
  45. Zhu X., Ohtsubo M., Böhmer R. M., Roberts J. M., Assoian R. K. Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein. J Cell Biol. 1996 Apr;133(2):391–403. doi: 10.1083/jcb.133.2.391. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES