Skip to main content
SpringerLink
Log in

Cyclin D1 in Breast Cancer

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Cyclin D1 protein plays an important part in regulating the progress of the cell during the G1 phase of the cell cycle. The cyclin D1 gene, CCND1, is amplified in approximately 20% of mammary carcinomas, and the protein is over- expressed in approximately 50% of cases. This has led to intensive study to ascertain whether cyclin D1 is a biological marker in breast cancer; however, the clinical work has produced unexpected results. Work in cell lines and in transgenic mice indicate that CCND1 is a weak oncogene and it was expected that, like c- erbB-2, over-expression of cyclin D1 protein would be associated with a poor prognosis. Early immunohistochemical prognostic studies produced equivocal results but we, and others, have recently shown that strong staining for cyclin D1 is more likely to be seen in well differentiated, estrogen receptor positive carcinomas. Furthermore, we have found that over-expression of cyclin D1 is actually associated with a good outcome, both in terms of prognosis and response to endocrine treatment. Cyclin D1 is frequently over- expressed in ductal carcinoma in situ but not in benign breast disease, including atypical ductal hyperplasia; hence its expression appears to be closely linked with carcinogenesis. In order to help explain the apparent beneficial effects of cyclin D1 over- expression, a number of closely associated cell cycle proteins have also been evaluated, including the cyclin dependent kinase inhibitor p27, which blocks the activating effects of cyclin D1. Initial reports show that high levels of p27 are associated with a good prognosis and we have shown a positive association between p27 and cyclin D1 expression. These clinical results of cyclin D1 are an example of how information obtained from basic cell biology studies needs to be complemented by clinical studies to ascertain the true worth of a prognostic marker.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bartkova J, Lukas J, Strauss M, Bartek J: Cell cycle related variation and tissue restricted expression of human cyclin D1 protein. J Pathol 172:237-245, 1994

    Google Scholar 

  2. Casey G, Smith R, McGillivray D, Peters G, Dickson C: Characterization and chromosome assignment of the human homolog of int-2, a potential proto-oncogene. Mol Cell Biol 6:502-510, 1986

    Google Scholar 

  3. Peters G: Inappropriate expression of growth factor genes in tumors induced by mouse mammary tumor virus. Semin Virol 2:319-328, 1991

    Google Scholar 

  4. Dickson C, Fantl V, Gillett C, Brookes S, Bartek J, Smith R, Fisher C, Barnes D, Peters G: Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer. Cancer (Letters) 90:43-50, 1995

    Google Scholar 

  5. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF: Studies of HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707-712, 1989

    Google Scholar 

  6. Borg Å, Sigurdsson H, Clark GM, Fernö M, Fuqua SAW, Olsson H, Killander D, McGuire WL: Association of INT2/HST1 co-amplification in primary breast cancer with hormone-dependent phenotype and poor prognosis. Br J Cancer 63:136-142, 1991

    Google Scholar 

  7. Schuuring E, Verhoeven E, van Tinteren H, Peterse JL, Nunnink B, Thunnissen FBJM, Devilee P, Cornelisse CJ, van der Vijver M, Mooi WJ, Michalides RJAM: Amplification of genes within the chromosome 11q13 region is indicative of poor prognosis in patients with operable breast cancer. Cancer Res 52:5229-5234, 1992

    Google Scholar 

  8. Fantl V, Richards MA, Smith R, Lammie GA, Johnstone G, Allen D, Gregory W, Peters G, Dickson C, Barnes DM: Gene amplification on chromosome band 11q13 and oestrogen receptor status in breast cancer. Eur J Cancer 26:423-429, 1990

    Google Scholar 

  9. Lammie GA, Fantl V, Smith R, Schuuring E, Brookes S, Michalides R, Dickson C, Arnold A, Peters G: D11S287, a putative oncogene on chromosome 11q13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL-1. Oncogene 6:439-444, 1991

    Google Scholar 

  10. Schuuring E, Verhofen E, Mooi WJ, Michalides R: Identification and cloning of two over-expressed genes, U21B31/PRAD1 and EMS1, within the amplified 11q13 region in human carcinomas. Oncogene 7:355-361, 1992

    Google Scholar 

  11. Gillett CE, Fantl V, 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 54:1812-1817, 1994

    Google Scholar 

  12. Buckley MF, Sweeney KJE, Hamilton JA, Sini RL, Manning DL, Nicholson RI, deFazio A, Watts CKW, Musgrove EA, Sutherland RL: Expression and amplification of cyclin genes in human breast cancer. Oncogene 8:2127-2133, 1993

    Google Scholar 

  13. Fantl V, Smith R, Brookes S, Dickson C, Peters G: Chromosome 11q13 abnormalities in human breast cancer. Cancer Surveys 18:77-94, 1993

    Google Scholar 

  14. Seshadri R, Lee CSL, Hui R, McCaul K, Horsfall DJ, Sutherland RL: Cyclin D1 amplification is not associated with reduced overall survival in primary breast cancer but may predict early relapse in patients with features of good prognosis. Clin Cancer Res 2:1177-1184, 1996

    Google Scholar 

  15. Barbareschi M, Pelosio P, Caffo O, Buttitta F, Pellegrini S, Barbazza R, Dalla Palma P, Bevilacqua G, Marchetti A: Cyclin D1 gene amplification and expression in breast carcinoma: relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21waf1 immunohistochcmical expression. Int J Cancer 74:171-174, 1997

    Google Scholar 

  16. Hui R, Cornish AL, McLelland RA, Robertson JFR, Blamey RW, Musgrove EA, Nicholson RI, Sutherland RL: Cyclin D1 and estrogen receptor messenger RNA levels are positively correlated in primary breast cancer. Clin Cancer Res 2:923-928, 1996

    Google Scholar 

  17. Weinstat-Saslow D, Merino MJ, Manrow RE, Lawrence JA, Bluth RF, Wittenbel KD, Simpson JF, Page DL, Steeg PS: Overexpression of cyclin D1 mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions. Nature Med 1:1257-1260, 1995

    Google Scholar 

  18. Zhang S-Y, Caamano J, Cooper F, Guo X, Klein-Szanto AJP: Immunohistochemistry of cyclin D1 in human breast cancer. Am J Clin Pathol 102:695-698, 1994

    Google Scholar 

  19. Nielsen NH, Emdin SO, Cajander J, Landberg G: Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein. Oncogene 14:295-304, 1997

    Google Scholar 

  20. Simpson JF, Quan DE, O'Malley F, Odom-Maryon T, Clarke PE: Amplification of CCND1 and expression of its protein product, cyclin D1, in ductal carcinoma in situ of the breast. Am J Pathol 151:161-168, 1997

    Google Scholar 

  21. Weinberg RA: The retinoblastoma protein and cell cycle control. Cell 81:323-330, 1995

    Google Scholar 

  22. Evans T, Rosenthal ET, Youngblom J, Distel X, Hunt T: Cyclin: a protein specified by material mRNA in sea urchin eggs that is destroyed at the end of each cell division. Cell 33:389-396, 1983

    Google Scholar 

  23. Sherr CJ: Mammalian G1 cyclins. Cell 73:1059-1065, 1993

    Google Scholar 

  24. Morgan DO: Principles of CDK regulation. Nature 374:131-134, 1995

    Google Scholar 

  25. Pardee AB: G1 events and regulation of cell proliferation. Science 246:603-608, 1989

    Google Scholar 

  26. Peters G: Stifled by inhibitions. Natures 371:204-205, 1994

    Google Scholar 

  27. Biggs JR, Kraft AS: Inhibitors of cyclin-dependent kinase and cancer. J Mol Med 73:509-514, 1995

    Google Scholar 

  28. Sherr CJ: Cancer cell cycles. Science 274:1672-1677, 1996

    Google Scholar 

  29. LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E: New functional activities for the p21 family of CDK inhibitors. Genes Devel 11:847-862, 1997

    Google Scholar 

  30. Zetterberg A, Larsson O, Wiman KG: What is the restriction point? Curr Opin Cell Biol 7:835-842, 1995

    Google Scholar 

  31. Fredersdorf S, Burns J, Milne AM, Packham G, Fallis L, Gillett CE, Royds JA, Peston D, Hall PA, Hanby AM, Barnes DM, Shousha S, O'Hare MJ, Lu X: High level expression of p27kip1 and cyclin D1 in some human breast cancer cells: inverse correlation between the expression of p27kip1 and degree of malignancy in human breast and colorectal cancers. Proc Natl Acad Sci USA 94:6380-6385, 1997

    Google Scholar 

  32. Assoian RK, Zhu X: Cell anchorage and the cytoskeleton as partners in growth factor dependent cell cycle progression. Curr Opin Cell Biol 9:93-98, 1997

    Google Scholar 

  33. Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE: Cyclin E-CDK2 is a regulator of p27kip1. Genes Devel 11:1464-1478, 1997

    Google Scholar 

  34. Vlach J, Hennecke S, Amati B: Phosphorylation-dependent degradation of the cyclin dependent kinase inhibitor p27kip1. EMBO J 16:5334-5344, 1997

    Google Scholar 

  35. Juan G, Gong J, Traganos F, Darzynkiewicz Z: Unscheduled expression of cyclins D1 and D3 in human tumour cell lines. Cell Prolif 29:259-266, 1996

    Google Scholar 

  36. Sewing A, Burger C, Brusselbach S, Schalk C, Lucibello FC, Muller R: Human cyclin D1 encodes a labile nuclear protein whose synthesis is directly induced by growth factors and suppressed by cyclic AMP. J Cell Sci 104:545-554, 1993

    Google Scholar 

  37. Musgrove EA, Hamilton JA, Lee CSL, Sweeny KJE, Watts CKW, Sutherland RL: 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 13:3577-3587, 1993

    Google Scholar 

  38. Pusch O, Soucek T, Wawra E, Hengstschlager-Ottnad E, Bernaschek G, Hengstschlager M: Specific transformation abolishes cyclin D1 fluctuation throughout the cell cycle. FEBS Lett 385:143-148, 1996

    Google Scholar 

  39. Zhu X, Ohtsubo M, Böhmer RM, Roberts JM, Assoian RK: 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 133:391-403, 1996

    Google Scholar 

  40. Atadja P, Wong H, Veillete C, Riabowol K: Over-expression of cyclin D1 blocks proliferation of normal diploid fibroblasts. Exp Cell Res 217:205-216, 1995

    Google Scholar 

  41. Kyo-Ho Han E, Begemann M, Sgambato A, Soh J-W, Doki Y, Xing W-Q, Liu W, Weinstein IB: Increased expression of cyclin D1 in a murine mammary epithelial cell line induces p27kip1, inhibits growth and enhances apoptosis. Cell Growth Differ 7:699-710, 1996

    Google Scholar 

  42. Lovec H, Sewing A, Lucibello FC, Muller R, Moroy T: Oncogenic activity of cyclin D1 revealed through cooperation with Ha-ras linke between cell cycle and malignant transformation. Oncogene 9:323-326, 1994

    Google Scholar 

  43. Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Harris AW, Adams JM: Cyclin D1 transgene impedes lymphocytic maturation and collaborates in lymphomagenesis with the myc gene. EMBO J 13:2124-2130, 1994

    Google Scholar 

  44. Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV: Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369:669-671, 1994

    Google Scholar 

  45. Fantl V, Stamp G, Andrews A, Rosewell I, Dickson C: Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Devel 9:2364-2372, 1995

    Google Scholar 

  46. Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, Haslam SZ, Bronson RT, Elledge SJ, Weinberg RA: Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621-630, 1995

    Google Scholar 

  47. 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 57:353-361, 1994

    Google Scholar 

  48. 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 9:707-718, 1994

    Google Scholar 

  49. Gillett C, Smith P, Gregory W, Richards M, Millis R, Peters G, Barnes D: Cyclin D1 and prognosis in human breast cancer. Int J Cancer 69:92-99, 1996

    Google Scholar 

  50. Nishio M, Koshikawa T, Yatabe Y, Kuroishi T, Suyama M, Nagatake M, Sugiura T, Ariyoshi Y, Mitsudomi T, Takahashi 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 3:1051-1058, 1997

    Google Scholar 

  51. van Diest P, Michalides RJAM, Jannink I, van der Valk P, Meijer CJLM, Baak JPA: Cyclin D1 expression in invasive breast cancer. Am J Pathol 150:705-711, 1997

    Google Scholar 

  52. 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 USA 91:2945-2949, 1994

    Google Scholar 

  53. Bates S, Parry D, Bonetta L, Vousden K, Dickson C: Absence of cyclin D/cdk complexes in cells lacking in functional retinoblastoma protein. Oncogene 9:1633-1640. 1994

    Google Scholar 

  54. Herwig S, Strauss M: The retinoblastoma protein: a master regulator of cell cycle, differentiation and apoptosis. Eur J Biochem 246:581-601, 1997

    Google Scholar 

  55. Dublin EA, Patel NK, Gillett CE, Smith P, Peters G, Barnes DM: Retinoblastoma and p16 proteins in mammary carcinoma: their relationship to cyclin D1 and histopathological parameters. Int J Cancer (Pred. Oncol.) 79:71-75, 1998

    Google Scholar 

  56. Pietiläinen T, Lipponen P, Aaltomaa S, Eskelinen M, Kosma VM, Syrjänen K: Expression of retinoblastoma gene protein (Rb) in breast cancer as related to established prognostic factors and survival. Eur J Cancer 31A:329-333, 1995

    Google Scholar 

  57. Sutherland RL, Prall OWJ, Alle KM, Wilcken NRC, Hui R, Ball JR, Sarcevic B, Henshall SM, Musgrove EA, Watts CKW: Cyclin-dependent kinases as downstream targets of oestrogen action: potential prognostic indicators and therapeutic targets. Endocrine Related Cancer 4:357-370, 1997

    Google Scholar 

  58. Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M, Ewen ME: Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Mol Cell Biol 17:5338-5347, 1997

    Google Scholar 

  59. Wilcken NRC, Prall OWJ, Musgrove EA, Sutherland RL: Inducible overexpression of cyclin D1 in breast cancer cells reduces the growth-inhibitory effects of antiestrogens. Clin Cancer Res 3:849-854, 1997

    Google Scholar 

  60. Paech K, Webb P, Kuiper GGJM, Nilsson S, Gustafsson J-Å, Kushner PJ, Scanlan TS: Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 277:1508-1510, 1997

    Google Scholar 

  61. Gillett C, Lee AHS, Barnes DM: Cycline D1 and associated proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia. J Pathol 184:396-400, 1998

    Google Scholar 

  62. Steeg PS, Abrams JS: Cancer prognostics: past, present and p27. Nature Med 3:152-154, 1997

    Google Scholar 

  63. Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L, Franssen E, Pritchard KI, Slingerland JM: Decreased levels of the cell-cycle inhibitor p27kip1 protein: prognostic implications in primary breast cancer. Nature Med 3:227-230, 1997

    Google Scholar 

  64. Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ, Daling JR, Roberts JM: Expression of cell cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nature Med 3:222-225, 1997

    Google Scholar 

  65. Tan P, Cady B, Wanner M, Worland P, Cukor B, Magi-Galluzzi C, Lavin P, Draetta G, Pagano M, Loda M: The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a,b) invasive breast carcinomas. Cancer Res 57:1259-1263, 1997

    Google Scholar 

  66. Zukerberg LR, Yang WI, Gadd M, Thor AD, Koerner FC, Schmidt EV, Arnold A: Cyclin D1 (PRAD1) protein expression in breast cancer: approximately one-third of infiltrating mammary carcinomas show over-expression of the cyclin D1 oncogene. Modern Pathol 8:560-567, 1995

    Google Scholar 

  67. McIntosh GG, Anderson JJ, Milton I, Steward M, Parr AH, Thomas MD, Henry JA, Angus B, Lennard TWJ, Horne CHW: Determination of the prognostic value of cyclin D1 overexpression in breast cancer. Oncogene 11:885-891, 1995

    Google Scholar 

  68. Michalides R, Hageman P, van Tinteren H, Houben L, Wientjens E, Klompmaker R, Peterse J: A clinicopathological study on overexpression of cyclin D1 and of p53 in a series of 248 patients with operable breast cancer. Br J Cancer 73:728-734, 1996

    Google Scholar 

  69. Pelosio P, Barbareschi M, Bonoldi E, Marchetti A, Verderio P, Caffo O, Bevilacqua P, Boracchi P, Buttitta F, Barbazza R, Palma PD, Gasparini G: Clinical significance of cyclin D1 expression in patients with node-positive breast carcinoma treated with adjuvant therapy. Ann Oncol 7:695-705, 1996

    Google Scholar 

Download references

Authors
  1. Diana M. Barnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cheryl E. Gillett
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barnes, D.M., Gillett, C.E. Cyclin D1 in Breast Cancer. Breast Cancer Res Treat 52, 1–15 (1998). https://doi.org/10.1023/A:1006103831990

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006103831990

Search

Navigation