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Cyclins and breast cancer

  • Patricia S. Steeg
  • Qun Zhou

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.

Key words

cyclin D cyclin E DCIS prevention tumor progression 

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References

  1. 1.
    Sherr C: Cancer cell cycles. Science 274:1672–1677, 1996PubMedCrossRefGoogle Scholar
  2. 2.
    Gao C, Zelenka P: Cyclins, cyclin-dependent kinases and differentiation. Bioessays 19:307–315, 1997PubMedCrossRefGoogle Scholar
  3. 3.
    T1sty T: Genomic instability and its role in neoplasia. Curr Top Microbiol 221:37–46, 1997CrossRefGoogle Scholar
  4. 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, 1997PubMedCrossRefGoogle Scholar
  5. 5.
    Hunter T, Pines J: Cyclins and cancer II: Cyclin D and CDK inhibitors come of age. Cell 79:573–582, 1994PubMedCrossRefGoogle Scholar
  6. 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, 1997PubMedCrossRefGoogle Scholar
  7. 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, 1997PubMedGoogle Scholar
  8. 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, 1995PubMedCrossRefGoogle Scholar
  9. 9.
    Zhou P, Jiang W, Weghorst CM, Weinstein IB: Overexpression of cyclin D1 enhances gene amplification. Cancer Res 56:36–39, 1996PubMedGoogle Scholar
  10. 10.
    Pagano M, Theodoras AM, Tarn SW, Draetta GF: Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts. Genes Devel 8:1627–1639, 1994PubMedCrossRefGoogle Scholar
  11. 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, 1992PubMedCrossRefGoogle Scholar
  12. 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, 1997PubMedCrossRefGoogle Scholar
  13. 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, 1994PubMedCrossRefGoogle Scholar
  14. 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, 1996PubMedGoogle Scholar
  15. 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, 1994PubMedCrossRefGoogle Scholar
  16. 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, 1995PubMedCrossRefGoogle Scholar
  17. 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, 1995PubMedCrossRefGoogle Scholar
  18. 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, 1994PubMedGoogle Scholar
  19. 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, 1993PubMedCrossRefGoogle Scholar
  20. 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, 1997PubMedCrossRefGoogle Scholar
  21. 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, 1993PubMedGoogle Scholar
  22. 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, 1995PubMedCrossRefGoogle Scholar
  23. 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, 1994PubMedGoogle Scholar
  24. 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, 1994PubMedCrossRefGoogle Scholar
  25. 25.
    Musgrove E, Sarcevic B, Sutherland R: Inducible expression of cyclin D1 in T-47D human breast cancer cells is sufficient for cdk2 activation and pRB hyperphosphorylation. J Cell Biochem 60:363–378, 1996PubMedCrossRefGoogle Scholar
  26. 26.
    Wilcken N, Prall O, Musgrove E, Sutherland R: Inducible overexpression of cyclin D1 in breast cancer cells reverses the growth inhibitory effects of anti-estrogens. Clin Cancer Res 3:849–854, 1997PubMedGoogle Scholar
  27. 27.
    Zwijsen RM, Klompmaker R, Wientjens EB, Kristel PM, van der Burg B, Michalides RJ: Cyclin D1 triggers autonomous growth of breast cancer cells by governing cell cycle exit. Mol Cell Biol 16:2554–2560, 1996PubMedGoogle Scholar
  28. 28.
    Bartkova J, Lukas J, Müller H, Lutzhoft D, Strauss M, Bartek J: Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 57:353–361, 1994PubMedCrossRefGoogle Scholar
  29. 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, 1994PubMedGoogle Scholar
  30. 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, 1996PubMedGoogle Scholar
  31. 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, 1995PubMedGoogle Scholar
  32. 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, 1996PubMedGoogle Scholar
  33. 33.
    Barnes D: Cyclin D1 in mammary carcinoma. J Pathol 181:267–269, 1997PubMedCrossRefGoogle Scholar
  34. 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, 1997PubMedCrossRefGoogle Scholar
  35. 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, 1995Google Scholar
  36. 36.
    Michalides R, Hageman P, van Tinteren H, Houben L, Wientjens E, Klompmaker R, Peterse J: A clinico-pathological 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, 1996PubMedCrossRefGoogle Scholar
  37. 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, 1997PubMedCrossRefGoogle Scholar
  38. 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, 1990CrossRefGoogle Scholar
  39. 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, 1992PubMedCrossRefGoogle Scholar
  40. 40.
    Elledge S, Harper J: Cdk inhibitors: on the threshold of checkpoints and development. Curr Opin Cell Biol 6:847–852, 1994PubMedCrossRefGoogle Scholar
  41. 41.
    Hunter T: Breaking the cycle. Cell 75:839–841, 1995CrossRefGoogle Scholar
  42. 42.
    Sherr C, Roberts J: Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Devel 9:1149–1163, 1995PubMedCrossRefGoogle Scholar
  43. 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, 1993PubMedCrossRefGoogle Scholar
  44. 44.
    Weinberg R: The retinoblastoma protein and cell cycle control. Cell 81:323–330, 1995PubMedCrossRefGoogle Scholar
  45. 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, 1995PubMedGoogle Scholar
  46. 46.
    Ohtsubo M, Roberts J: Cyclin-dependent regulation of G1 in mammalian fibroblasts. Science 259:1908–1912, 1993PubMedCrossRefGoogle Scholar
  47. 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, 1997PubMedGoogle Scholar
  48. 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, 1995PubMedGoogle Scholar
  49. 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, 1995PubMedGoogle Scholar
  50. 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, 1995PubMedCrossRefGoogle Scholar
  51. 51.
    Keyomarsi K, Pardee A: Redundant cyclin over-expression and gene amplification in breast cancer cells. Proc Natl Acad Sci USA 90:1112–1116, 1993PubMedCrossRefGoogle Scholar
  52. 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, 1996PubMedCrossRefGoogle Scholar
  53. 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, 1996PubMedCrossRefGoogle Scholar
  54. 54.
    Sewing A, Ronicke Y, Burger C, Funk M, Muller R: Alternative splicing of cyclin E. J Cell Sci 107:581–588, 1994PubMedGoogle Scholar
  55. 55.
    Keyomarsi K, Conte D Jr, Toyofuku W, Fox MP: Deregulation of cyclin E in breast cancer. Oncogene 11:941–950. 1995PubMedGoogle Scholar
  56. 56.
    Won K-A, Reed S: Activation of cyclin E/CDK2 is coupled to site-specific autophosphorylation and ubi-quitin-dependent degradation of cyclin E. EMBO J 15:4182–4193, 1996PubMedGoogle Scholar
  57. 57.
    Sgambato A, Doki Y, Schieren I, Weinstein IB: Effects of cyclin E overexpression on cell growth and response to transforming growth factor ß depend on cell context and p27kip1 expression. Cell Growth Diff 8:393–405, 1997PubMedGoogle Scholar
  58. 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, 1996PubMedCrossRefGoogle Scholar
  59. 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, 1997PubMedCrossRefGoogle Scholar
  60. 60.
    Scott K, Walker R: Lack of cyclin E immunoreactiv-ity in non-malignant breast and association with proliferation in breast cancer. Br J Cancer 76:1288–1292, 1997PubMedCrossRefGoogle Scholar
  61. 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, 1997Google Scholar
  62. 62.
    Page D, DuPont W: Anatomic indicators (histologie and cytologie) of increased breast cancer risk. Breast Cancer Res Treat 28:157–166, 1993PubMedCrossRefGoogle Scholar
  63. 63.
    Page D, DuPont W: Anatomic markers of human pre-malignancy and risk of breast cancer. Cancer 66:1326–1335, 1990PubMedCrossRefGoogle Scholar
  64. 64.
    DuPont W, Page D: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312:146–151, 1985PubMedCrossRefGoogle Scholar
  65. 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, 1995PubMedCrossRefGoogle Scholar
  66. 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, 1996PubMedGoogle Scholar
  67. 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, 1997PubMedGoogle Scholar
  68. 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, 1998PubMedCrossRefGoogle Scholar
  69. 69.
    Stanta G, Bonin S, Losa L, Eusebi V: Molecular characterization of intraductal breast carcinomas. Virchows Arch 432:107–111, 1998PubMedCrossRefGoogle Scholar
  70. 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, 1997PubMedCrossRefGoogle Scholar
  71. 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, 1994PubMedGoogle Scholar
  72. 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, 1995PubMedGoogle Scholar
  73. 73.
    Lotan R: Retinoids in cancer chemoprevention. FASEB J 10:1031–1039, 1996PubMedGoogle Scholar
  74. 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, 1995CrossRefGoogle Scholar
  75. 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, 1994PubMedGoogle Scholar
  76. 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, 1997PubMedCrossRefGoogle Scholar
  77. 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, 1996PubMedGoogle Scholar
  78. 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, 1997PubMedCrossRefGoogle Scholar
  79. 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, 1997PubMedGoogle Scholar
  80. 80.
    Ligueros M, Jeoung D, Tang B, Hochhäuser D, Reidenberg M, Sonenberg M: Gossypol inhibition of mitosis, cyclin D1 and Rb protein in human mammary cancer cells and cyclin-D1 transfected human fibro-sarcoma cells. Br J Cancer 76:21–28, 1997PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1998

Authors and Affiliations

  • Patricia S. Steeg
    • 1
  • Qun Zhou
    • 1
    • 2
  1. 1.Women’ s Cancers Section, Laboratory of Pathology, Division of Clinical SciencesNational Cancer InstituteBethesdaUSA
  2. 2.Women’ s Cancers Section, Laboratory of Pathology, Division of Clinical SciencesNational Cancer InstituteBethesdaUSA

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