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. 1996 Mar;73(6):728–734. doi: 10.1038/bjc.1996.128

A clinicopathological study on overexpression of cyclin D1 and of p53 in a series of 248 patients with operable breast cancer.

R Michalides 1, P Hageman 1, H van Tinteren 1, L Houben 1, E Wientjens 1, R Klompmaker 1, J Peterse 1
PMCID: PMC2074376  PMID: 8611372

Abstract

Overexpression of cyclin D1 is frequently found in various types of human tumours and results from clonal rearrangement and/or amplification involving chromosomal region 11q13. In order to evaluate the pathological relevance of cyclin D1 overexpression in human breast cancer, we generated a polyclonal antiserum against the carboxy-terminal part of the cyclin D1 protein. After affinity purification, the antiserum specifically detected overexpression of cyclin D1 in formalin-fixed, paraffin-embedded tumour material also. The intensity of the nuclear stainings was, in general, proportional to the degree of cyclin D1 amplification. We did not encounter significant variability of staining within individual tumours with overexpression of cyclin D1. Overexpression of cyclin D1 appeared to be associated with oestrogen receptor-positive breast tumours, but not with any other clinicopathological parameter tested. Overexpression of cyclin D1 was not prognostic value for recurrence of survival in a consecutive series of 248 operable breast cancer patients (stage I and II). Overexpression of p53 was also not of prognostic significance in this series, but was associated with undifferentiated histology and oestrogen receptor-negative breast tumours, as has been reported previously by others. A high proportion of breast tumours with a low grade of malignancy in this series of operable breast cancer patients may explain discrepancies concerning the prognostic value of amplification and of overexpression of cyclin D1.

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Selected References

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  1. Bartkova J., Lukas J., Müller H., Lützhøft D., Strauss M., Bartek J. Cyclin D1 protein expression and function in human breast cancer. Int J Cancer. 1994 May 1;57(3):353–361. doi: 10.1002/ijc.2910570311. [DOI] [PubMed] [Google Scholar]
  2. Bishop J. M. The molecular genetics of cancer. Science. 1987 Jan 16;235(4786):305–311. doi: 10.1126/science.3541204. [DOI] [PubMed] [Google Scholar]
  3. Bodrug S. E., Warner B. J., Bath M. L., Lindeman G. J., Harris A. W., Adams J. M. Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. EMBO J. 1994 May 1;13(9):2124–2130. doi: 10.1002/j.1460-2075.1994.tb06488.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Borg A., Sigurdsson H., Clark G. M., Fernö M., Fuqua S. A., Olsson H., Killander D., McGurie W. L. Association of INT2/HST1 coamplification in primary breast cancer with hormone-dependent phenotype and poor prognosis. Br J Cancer. 1991 Jan;63(1):136–142. doi: 10.1038/bjc.1991.28. [DOI] [PMC free article] [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. Cornelis R. S., van Vliet M., Vos C. B., Cleton-Jansen A. M., van de Vijver M. J., Peterse J. L., Khan P. M., Børresen A. L., Cornelisse C. J., Devilee P. Evidence for a gene on 17p13.3, distal to TP53, as a target for allele loss in breast tumors without p53 mutations. Cancer Res. 1994 Aug 1;54(15):4200–4206. [PubMed] [Google Scholar]
  7. Davidoff A. M., Kerns B. J., Iglehart J. D., Marks J. R. Maintenance of p53 alterations throughout breast cancer progression. Cancer Res. 1991 May 15;51(10):2605–2610. [PubMed] [Google Scholar]
  8. Ebina M., Steinberg S. M., Mulshine J. L., Linnoila R. I. Relationship of p53 overexpression and up-regulation of proliferating cell nuclear antigen with the clinical course of non-small cell lung cancer. Cancer Res. 1994 May 1;54(9):2496–2503. [PubMed] [Google Scholar]
  9. Elston C. W., Ellis I. O. Pathology and breast screening. Histopathology. 1990 Feb;16(2):109–118. doi: 10.1111/j.1365-2559.1990.tb01078.x. [DOI] [PubMed] [Google Scholar]
  10. Faille A., De Cremoux P., Extra J. M., Linares G., Espie M., Bourstyn E., De Rocquancourt A., Giacchetti S., Marty M., Calvo F. p53 mutations and overexpression in locally advanced breast cancers. Br J Cancer. 1994 Jun;69(6):1145–1150. doi: 10.1038/bjc.1994.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fantl V., Richards M. A., Smith R., Lammie G. A., Johnstone G., Allen D., Gregory W., Peters G., Dickson C., Barnes D. M. Gene amplification on chromosome band 11q13 and oestrogen receptor status in breast cancer. Eur J Cancer. 1990 Apr;26(4):423–429. doi: 10.1016/0277-5379(90)90009-i. [DOI] [PubMed] [Google Scholar]
  12. Frye R. A., Benz C. C., Liu E. Detection of amplified oncogenes by differential polymerase chain reaction. Oncogene. 1989 Sep;4(9):1153–1157. [PubMed] [Google Scholar]
  13. Gillett C., Fantl V., Smith R., Fisher C., Bartek J., Dickson C., Barnes D., Peters G. Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res. 1994 Apr 1;54(7):1812–1817. [PubMed] [Google Scholar]
  14. Greenwell A., Foley J. F., Maronpot R. R. An enhancement method for immunohistochemical staining of proliferating cell nuclear antigen in archival rodent tissues. Cancer Lett. 1991 Sep;59(3):251–256. doi: 10.1016/0304-3835(91)90149-c. [DOI] [PubMed] [Google Scholar]
  15. Harris C. C., Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med. 1993 Oct 28;329(18):1318–1327. doi: 10.1056/NEJM199310283291807. [DOI] [PubMed] [Google Scholar]
  16. Henry J. A., Hennessy C., Levett D. L., Lennard T. W., Westley B. R., May F. E. int-2 amplification in breast cancer: association with decreased survival and relationship to amplification of c-erbB-2 and c-myc. Int J Cancer. 1993 Mar 12;53(5):774–780. doi: 10.1002/ijc.2910530512. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Keyomarsi K., Pardee A. B. Redundant cyclin overexpression and gene amplification in breast cancer cells. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):1112–1116. doi: 10.1073/pnas.90.3.1112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lammie G. A., Peters G. Chromosome 11q13 abnormalities in human cancer. Cancer Cells. 1991 Nov;3(11):413–420. [PubMed] [Google Scholar]
  20. Levine A. J., Perry M. E., Chang A., Silver A., Dittmer D., Wu M., Welsh D. The 1993 Walter Hubert Lecture: the role of the p53 tumour-suppressor gene in tumorigenesis. Br J Cancer. 1994 Mar;69(3):409–416. doi: 10.1038/bjc.1994.76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Lönn U., Lönn S., Nilsson B., Stenkvist B. Breast cancer: prognostic significance of c-erb-B2 and int-2 amplification compared with DNA ploidy, S-phase fraction, and conventional clinicopathological features. Breast Cancer Res Treat. 1994;29(3):237–245. doi: 10.1007/BF00666477. [DOI] [PubMed] [Google Scholar]
  23. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966 Mar;50(3):163–170. [PubMed] [Google Scholar]
  24. Marchetti A., Buttitta F., Pellegrini S., Campani D., Diella F., Cecchetti D., Callahan R., Bistocchi M. p53 mutations and histological type of invasive breast carcinoma. Cancer Res. 1993 Oct 1;53(19):4665–4669. [PubMed] [Google Scholar]
  25. Michalides R., van Veelen N., Hart A., Loftus B., Wientjens E., Balm A. Overexpression of cyclin D1 correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Cancer Res. 1995 Mar 1;55(5):975–978. [PubMed] [Google Scholar]
  26. Motokura T., Arnold A. Cyclins and oncogenesis. Biochim Biophys Acta. 1993 May 25;1155(1):63–78. doi: 10.1016/0304-419x(93)90022-5. [DOI] [PubMed] [Google Scholar]
  27. Musgrove E. A., Hamilton J. A., Lee C. S., Sweeney K. J., Watts C. K., Sutherland R. L. Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression. Mol Cell Biol. 1993 Jun;13(6):3577–3587. doi: 10.1128/mcb.13.6.3577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Quelle D. E., Ashmun R. A., Shurtleff S. A., Kato J. Y., Bar-Sagi D., Roussel M. F., Sherr C. J. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev. 1993 Aug;7(8):1559–1571. doi: 10.1101/gad.7.8.1559. [DOI] [PubMed] [Google Scholar]
  29. Schuuring E., Verhoeven E., Mooi W. J., Michalides R. J. Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas. Oncogene. 1992 Feb;7(2):355–361. [PubMed] [Google Scholar]
  30. Schuuring E., Verhoeven E., van Tinteren H., Peterse J. L., Nunnink B., Thunnissen F. B., Devilee P., Cornelisse C. J., van de Vijver M. J., Mooi W. J. Amplification of genes within the chromosome 11q13 region is indicative of poor prognosis in patients with operable breast cancer. Cancer Res. 1992 Oct 1;52(19):5229–5234. [PubMed] [Google Scholar]
  31. Sherr C. J. Mammalian G1 cyclins. Cell. 1993 Jun 18;73(6):1059–1065. doi: 10.1016/0092-8674(93)90636-5. [DOI] [PubMed] [Google Scholar]
  32. Silvestrini R., Benini E., Daidone M. G., Veneroni S., Boracchi P., Cappelletti V., Di Fronzo G., Veronesi U. p53 as an independent prognostic marker in lymph node-negative breast cancer patients. J Natl Cancer Inst. 1993 Jun 16;85(12):965–970. doi: 10.1093/jnci/85.12.965. [DOI] [PubMed] [Google Scholar]
  33. Thor A. D., Moore DH I. I., Edgerton S. M., Kawasaki E. S., Reihsaus E., Lynch H. T., Marcus J. N., Schwartz L., Chen L. C., Mayall B. H. Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst. 1992 Jun 3;84(11):845–855. doi: 10.1093/jnci/84.11.845. [DOI] [PubMed] [Google Scholar]
  34. Tsuda H., Hirohashi S., Shimosato Y., Hirota T., Tsugane S., Yamamoto H., Miyajima N., Toyoshima K., Yamamoto T., Yokota J. Correlation between long-term survival in breast cancer patients and amplification of two putative oncogene-coamplification units: hst-1/int-2 and c-erbB-2/ear-1. Cancer Res. 1989 Jun 1;49(11):3104–3108. [PubMed] [Google Scholar]
  35. Vogelstein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525–532. doi: 10.1056/NEJM198809013190901. [DOI] [PubMed] [Google Scholar]
  36. 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]

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