Skip to main content
SpringerLink
Log in

Cyclins and breast cancer

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

Abstract

Cyclins are regulatory subunits for cyclin dependent kinases in the coordination of the cell cycle. Cyclins can also serve non-cell cycle functions, such as the transactivation of estrogen receptor by cyclin D. Evidence for the participation of the G1 cyclins D and E in breast cancer is summarized, including transgenic and knockout mice, transfections, and expression patterns in cohort studies. Overexpression of cyclin D has been reported in ductal carcinoma in situ (DCIS), and similar overexpression of cyclin E is suggested. Strategies to reduce cyclin expression are discussed as potential prevention efforts.

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

    Google Scholar 

  2. Gao C, Zelenka P: Cyclins, cyclin-dependent kinases and differentiation. Bioessays 19:307-315, 1997

    Google Scholar 

  3. Tlsty T: Genomic instability and its role in neoplasia. Curr Top Microbiol 221:37-46, 1997

    Google Scholar 

  4. Sarcevic B, Lilischkis R, Sutherland R: Differential phosphorylation of T-47D human breast cancer cell substrates by D1-, D3-, E-and A-type cyclin-CDK complexes. J Biol Chem 272:33327-33337, 1997

    Google Scholar 

  5. Hunter T, Pines J: Cyclins and cancer II: Cyclin D and CDK inhibitors come of age. Cell 79:573-582, 1994

    Google Scholar 

  6. Zwijsen R, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides R: CDK-independent activation of estrogen receptor by cyclin D1. Cell 88:405-415, 1997

    Google Scholar 

  7. Neuman E, Ladha M, Lin N, Upton T, Miller S, Renzo JD, Pestell R, Hinds P, Dowdy S, Brown M, Ewen M: Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Mol Cell Biol 17:5338-5347, 1997

    Google Scholar 

  8. Asano K, Sakamoto H, Sasaki H, Ochiya T: Tumorigenicity and gene amplification potentials of cyclin D1-overexpressing NIH3T3 cells. Biochem Biophys Res Commun 217:1169-1176, 1995

    Google Scholar 

  9. Zhou P, Jiang W, Weghorst CM, Weinstein IB: Overexpression of cyclin D1 enhances gene amplification. Cancer Res 56:36-39, 1996

    Google Scholar 

  10. Pagano M, Theodoras AM, Tam SW, Draetta GF: Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts. Genes Devel 8:1627-1639, 1994

    Google Scholar 

  11. Xiong Y, Zhang H, Beach D: D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 71:505-514, 1992

    Google Scholar 

  12. Lahti J, Li H, Kidd V: Elimination of cyclin D1 in vertebrate cells leads to an altered cell cycle phenotype, which is rescued by overexpression of murine cyclins D1, D2, or D3 but not by a mutant cyclin D1. J Biol Chem 272:10859-10869, 1997

    Google Scholar 

  13. Freeman R, Estus S, Johnson EM Jr: Analysis of cell cycle-related gene expression in postmitotic neurons: Selective induction of cyclin D1 during programmed cell death. Neuron 12:343-355, 1994

    Google Scholar 

  14. Kranenburg O, van der Eb AJ, Zantema A: Cyclin D1 is an essential mediator of apoptotic neuronal cell death. EMBO J 15:46-54, 1996

    Google Scholar 

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

    Google Scholar 

  16. Sicinski P, Donaher J, Parker S, Li T, Fazeli A, Gardner H, Haslam S, Bronson R, Elledge S, Weinberg R: Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621-630, 1995

    Google Scholar 

  17. Fantl V, Stamp G, Andrews A, Roswell 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 

  18. Resnitzky D, Gossen M, Bujard H, Reed S: Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. Mol Cell Biol 14:1669-1679, 1994

    Google Scholar 

  19. Quelle D, Ashmun R, Shurtleff S, Kato J-Y, Bar-Sagi D, Roussel M, Scherr C: Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Devel 7:1559-1571, 1993

    Google Scholar 

  20. Hiyama H, Iavarone A, LaBaer J, Reeves S: Regulated ectopic expression of cyclin D1 induces transcriptional activation of the cdk inhibitor p21 gene without altering cell cycle progression. Oncogene 14:2533-2542, 1997

    Google Scholar 

  21. Jiang W, Kahn SM, Zhou P, Zhang Y, Cacace AM, Infante AS, Doi S, Santella RM, Weinstein IB: Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. Oncogene 8:3447-3457, 1993

    Google Scholar 

  22. Atadja P, Wong H, Veilete C, Riabowol K: Overexpression of cyclin D1 blocks proliferation of normal diploid fibroblasts. Exp Cell Res 217:205-216, 1995

    Google Scholar 

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

    Google Scholar 

  24. Musgrove E, Lee C, Buckley M, Sutherland R: Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. Proc Natl Acad Sci USA 91:8022-8026, 1994

    Google Scholar 

  25. Musgrove E, Sarcevic B, Sutherland R: Inducible expression of cyclin D1 in T-47D human breast cancer cells is sufficient for cdk2 activiation and pRB hyperphosphorylation. J Cell Biochem 60:363-378, 1996

    Google Scholar 

  26. Wilcken N, Prall O, Musgrove E, Sutherland R: Inducible overexpression of cyclin D1 in breast cancer cells reverses the growth inhibitory effects of antiestrogens. Clin Cancer Res 3:849-854, 1997

    Google Scholar 

  27. Zwijsen RM, Klompmaker R, Wientjens EB, Kristel PM, van der Burg B, Michaldes RJ: Cyclin D1 triggers autonomous growth of breast cancer cells by governing cell cycle exit. Mol Cell Biol 16:2554-2560, 1996

    Google Scholar 

  28. Bartkova J, Lukas J, Muller H, Lutzhoft D, Strauss M, Bartek J: Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 57:353-361, 1994

    Google Scholar 

  29. 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 

  30. Lukas J, Bartkova J, Bartek J: Convergence of mitogenic signalling cascades from diverse classes of receptors at the cyclin D-cyclin-dependent kinase-pRb-controlled G1 checkpoint. Mol Cell Biol 16:6917-6925, 1996

    Google Scholar 

  31. Han EK-H, Sgambato A, Jiang W, Zhang Y-J, San-tella R, Doki Y, Cacace A, Schieren I, Weinstein IB: Stable overexpression of cyclin D1 in a human mammary epithelial cell line prolongs the S-phase and inhibits growth. Oncogene 10:953-961, 1995

    Google Scholar 

  32. Han E-H, 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 Diff 7:699-710, 1996

    Google Scholar 

  33. Barnes D: Cyclin D1 in mammary carcinoma. J Pathol 181:267-269, 1997

    Google Scholar 

  34. Hui R, Campbell D, Lee C, McCaul K, Horsfall D, Musgrove E, Daly R, Seshadri R, Sutherland R: EMS1 amplification can occur independently of CCND1 or INT-2 amplification at 11q13 and may identify different phenoytpes in primary breast cancer. Oncogene 15:1617-1623, 1997

    Google Scholar 

  35. Zuckerberg L, Yang W, Gadd M, Thor A, Koerner F, Schmidt E, Arnold A: Cyclin D1 (PRAD1) protein expression in breast cancer: approximately one third of infiltrating mammary carcinomas show overexpression of the cyclin D1 oncogene. Mod Pathol 8:560-567, 1995

    Google Scholar 

  36. 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 

  37. 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 p21waf immunohistochemical expression. Int J Cancer 74:171-174, 1997

    Google Scholar 

  38. D'Urso C, Marracino R, Marshak D, Roberts J: Cell cycle control of DNA replication by a homologue from human cells of the p34cdc2 protein kinase. Science 250:786-791, 1990

    Google Scholar 

  39. Koff A, Giordano A, Desai D, Yamashita K, Harper J, Elledge S, Nishimoto T, Morgan D, Framza B, Roberts J: Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science 257:1689-1694, 1992

    Google Scholar 

  40. Elledge S, Harper J: Cdk inhibitors: on the threshold of checkpoints and development. Curr Opin Cell Biol 6:847-852, 1994

    Google Scholar 

  41. Hunter T: Breaking the cycle. Cell 75:839-841, 1995

    Google Scholar 

  42. Sherr C, Roberts J: Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Devel 9:1149-1163, 1995

    Google Scholar 

  43. Li Y, Graham C, Lacy S, Duncan A, Whyte P: The adenovirus E1A associated 130 KD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E. Genes Devel 7:2366-2377, 1993

    Google Scholar 

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

    Google Scholar 

  45. Ohtsubo M, Theodoras A, Schumacher J, Roberts J, Pagano M: Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol 15:2612-2624, 1995

    Google Scholar 

  46. Ohtsubo M, Roberts J: Cyclin-dependent regulation of G1 in mammalian fibroblasts. Science 259:1908-1912, 1993

    Google Scholar 

  47. Bortner D, Rosenberg M: Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. Mol Cell Biol 17:453-459, 1997

    Google Scholar 

  48. Resnitzky D, Reed S: Different roles for cyclins D1 and E in regulation of the G1-to-S transition. Mol Cell Biol 15:3463-3469, 1995

    Google Scholar 

  49. Lukas J, Bartkova J, Rohde M, Strauss M, Bartek J: Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity. Mol Cell Biol 15:2600-2611, 1995

    Google Scholar 

  50. Beijersbergen R, Carlee L, Kerhovn R, Bernards R: Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes. Genes Devel 9:1340-1353, 1995

    Google Scholar 

  51. Keyomarsi K, Pardee A: Redundant cyclin overexpression and gene amplification in breast cancer cells. Proc Natl Acad Sci USA 90:1112-1116, 1993

    Google Scholar 

  52. Courjal F, Louason G, Speiser P, Katasaros D, Zeillinger R, Theillet C: Cyclin gene amplification and overexpression in breast and ovarian cancers: evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors. Int J Cancer 69:247-253, 1996

    Google Scholar 

  53. Gray-Bablin J, Zalvide J, Fox M, Knickerbocker C, DeCaprio J, Keyomarsi K: Cyclin E, a redundant cyclin in breast cancer. Proc Natl Acad Sci USA 93:15215-15220, 1996

    Google Scholar 

  54. Sewing A, Ronicke Y, Burger C, Funk M, Muller R: Alternative splicing of cyclin E. J Cell Sci 107:581-588, 1994

    Google Scholar 

  55. Keyomarsi K, Conte D Jr, Toyofuku W, Fox MP: Deregulation of cyclin E in breast cancer. Oncogene 11:941-950, 1995

    Google Scholar 

  56. Won K-A, Reed S: Activation of cyclin E/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin E. EMBO J 15:4182-4193, 1996

    Google Scholar 

  57. Sgambato A, Doki Y, Schieren I, Weinstein IB: Effects of cyclin E overexpression on cell growth and response to transforming growth factor β depend on cell context and p27kip1 expression. Cell Growth Diff 8:393-405, 1997

    Google Scholar 

  58. Nielsen N, Arnerlov C, Emdin S, Landberg H: Cyclin E overexpression, a negative prognostic factor in breast cancer with a strong correlation to oestrogen receptor status. Br J Cancer 74:874-880, 1996

    Google Scholar 

  59. Porter P, Malone K, Heagerty P, Alexander G, Gatti L, Firpo E, Daling J, Roberts J: 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 

  60. Scott K, Walker R: Lack of cyclin E immunoreactivity in non-malignant breast and association with proliferation in breast cancer. Br J Cancer 76:1288-1292, 1997

    Google Scholar 

  61. Nielsen N, Emdin S, Cajander J, Landberg G: Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein. Br J Cancer 76:295-304, 1997

    Google Scholar 

  62. Page D, DuPont W: Anatomic indicators (histologic and cytologic) of increased breast cancer risk. Breast Cancer Res Treat 28:157-166, 1993

    Google Scholar 

  63. Page D, DuPont W: Anatomic markers of human premalignancy and risk of breast cancer. Cancer 66:1326-1335, 1990

    Google Scholar 

  64. DuPont W, Page D: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312:146-151, 1985

    Google Scholar 

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

    Google Scholar 

  66. Steeg PS, Clare SE, Lawrence JA, Zhou Q: Molecular analysis of premalignant and carcinoma in situ lesions of the human breast. Am J Pathol 149:733-738, 1996

    Google Scholar 

  67. Simpson J, Quan D, O'Malley F, Odom-Maryon T, Clarke P: 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 

  68. Gillett C, Lee A, Millis R, Barnes D: Cyclin D1 and associated proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia. J Pathol 184:396-400, 1998

    Google Scholar 

  69. Stanta G, Bonin S, Losa L, Eusebi V: Molecular characterization of intraductal breast carcinomas. Virchows Arch 432:107-111, 1998

    Google Scholar 

  70. Zhou Q, Stetler-Stevenson M, Steeg P: Inhibition of cyclin D expression in human breast carcinoma cells by retinoids in vitro. Oncogene 15:107-115, 1997

    Google Scholar 

  71. Rubin M, Fenig E, Rosenauer A, Menendez-Botet C, Achkar C, Bentel JM, Yahalom J, Mendelsohn J, Miller WH: 9-cis retinoic acid inhibits growth of breast cancer cells and down-regulates estrogen receptor RNA and protein. Cancer Res 54:6549-6556, 1994

    Google Scholar 

  72. Shao ZM, Dawson MI, Li XS, Rishi AK, Sheikh MS, Han QX, Ordonez JV, Shroot B, Fontana JA: p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. Oncogene 11:493-504, 1995

    Google Scholar 

  73. Lotan R: Retinoids in cancer chemoprevention. FASEB J 10:1031-1039, 1996

    Google Scholar 

  74. Zhao ZM, Sheikh MS, Rishi AK, Dawson MI, Li XS, Wilber JF, Feng P, Fontana JA: Effect of 9-cis-retinoic acid on growth and RXR expression in human breast cancer cells. Expt Cell Res 219:555-561, 1995

    Google Scholar 

  75. Anzano MA, Byers SW, Smith JM, Peer CW, Mullen LT, Brown CC, Roberts AB, Sporn MB: Prevention of breast cancer in the rat with 9-cis-retinoic acid as single agent and in combination with tamoxifen. Cancer Res 54:4614-4617, 1994

    Google Scholar 

  76. Zhu W-Y, Jones C, Kiss A, Matsukuma K, Amin S, DeLuca L: Retinoic acid inhibition of cell cycle progression in MCF-7 human breast cancer cells. Exp Cell Res 234:293-299, 1997

    Google Scholar 

  77. Wilcken N, Sarcevid B, Musgrove E, Sutherland R: Differential effects of retinoids and antiestrogens on cell cycle progression and cell cycle regulatory genes in human breast cancer cells. Cell Growth Diff 7:65-74, 1996

    Google Scholar 

  78. Teixeira C, Pratt M: CDK2 is a target for retinoic acid-mediated growth inhibition in MCF-7 human breast cancer cells. Mol Endocrinol 11:1191-1202, 1997

    Google Scholar 

  79. Seewaldt V, Kim J-H, Caldwell L, Johnson B, Swisshelm K, Collins S: All-trans-retinoic acid mediates G1 arrest but not apoptosis of normal human mammary epithelial cells. Cell Growth Diff 8:631-641, 1997

    Google Scholar 

  80. Ligueros M, Jeoung D, Tang B, Hochhauser D, Reidenberg M, Sonenberg M: Gossypol inhibition of mitosis, cyclin D1 and Rb protein in human mammary cancer cells and cyclin-D1 transfected human fibrosarcoma cells. Br J Cancer 76:21-28, 1997

    Google Scholar 

Download references

Authors
  1. Patricia S. Steeg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qun Zhou
    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

Steeg, P.S., Zhou, Q. Cyclins and breast cancer. Breast Cancer Res Treat 52, 17–28 (1998). https://doi.org/10.1023/A:1006102916060

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006102916060

Search

Navigation