Cell Cycle Machinery:

Links with Genesis and Treatment of Breast Cancer
  • Alison J. Butt
  • C. Elizabeth Caldon
  • Catriona M. McNeil
  • Alexander Swarbrick
  • Elizabeth A. Musgrove
  • Robert L. Sutherland
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 630)


Loss of normal growth control is a hallmark of cancer. Thus, understanding the mechanisms of tissue-specific, normal growth regulation and the changes that occur during tumorigenesis may provide insights of both diagnostic and therapeutic importance. Control of cell proliferation in the normal mammary gland is steroid hormone (estrogen and progestin)-dependent, involves complex interactions with other hormones, growth factors and cytokines and ultimately converges on activation of three proto-oncogenes (c-Myc, cyclin D1 and cyclin E1) that are rate limiting for the G1 to S phase transition during normal cell cycle progression. Mammary epithelial cell-specific overexpression of these genes induces mammary carcinoma in mice, while cyclin D1 null mice have arrested mammary gland development and are resistant to carcinoma induced by the neu/erbB2 and ras oncogenes. Furthermore, c-Myc, cyclins D1, E1 and E2 are commonly overexpressed in primary breast cancer where elevated expression is often associated with a more aggressive disease phenotype and an adverse patient outcome. This may be due in part to overexpression of these genes conferring resistance to endocrine therapies since in vitro studies provide compelling evidence that overexpression of c-Myc and to a lesser extent cyclin D1 and cyclin E1, attenuate the growth inhibitory effects of SERMS, antiestrogens and progestins in breast cancer cells. Thus, abnormal regulation of the expression of cell cycle molecules, involved in the steroidal control of cell proliferation in the mammary gland, are likely to be directly involved in the development, progression and therapeutic responsiveness of breast cancer. Furthermore, a more detailed understanding of these pathways may identify new targets for therapeutic intervention particularly in endocrine-unresponsive and endocrine-resistant disease.


Breast Cancer Breast Cancer Cell Mammary Gland Cell Cycle Machinery Mammary Gland Biol Neoplasia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57–70.PubMedGoogle Scholar
  2. 2.
    Harbour JW, Dean DC. Rb function in cell-cycle regulation and apoptosis. Nat Cell Biol 2000; 2:E65–7.PubMedGoogle Scholar
  3. 3.
    Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 2001; 1:222–31.PubMedGoogle Scholar
  4. 4.
    Morgan DO. Cyclin-dependent kinases: engines, clocks and microprocessors. Annu Rev Cell Dev Biol 1997; 13:261–91.PubMedGoogle Scholar
  5. 5.
    Garriga J, Grana X. Cellular control of gene expression by T-type cyclin/CDK9 complexes. Gene 2004; 337:15–23.PubMedGoogle Scholar
  6. 6.
    Coqueret O. Linking cyclins to transcriptional control. Gene 2002; 299:35–55.PubMedGoogle Scholar
  7. 7.
    Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999; 13:1501–12.PubMedGoogle Scholar
  8. 8.
    Sarcevic B, Lilischkis R, Sutherland RL. Differential phosphorylation of T-47D human breast cancer cell substrates by D1-, D3-, E-and A-type cyclin-CDK complexes. J Biol Chem 1997; 272:33327–37.PubMedGoogle Scholar
  9. 9.
    Kitagawa M, Higashi H, Jung HK et al. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. EMBO J 1996; 15:7060–9.PubMedGoogle Scholar
  10. 10.
    Sherr CJ, Roberts JM. Living with or without cyclins and cyclin-dependent kinases. Genes Dev 2004; 18:2699–711.PubMedGoogle Scholar
  11. 11.
    Murray AW. Recycling the cell cycle: cyclins revisited. Cell 2004; 116:221–34.PubMedGoogle Scholar
  12. 12.
    Lukas J, Bartkova J, Rohde M et al. Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity. Mol Cell Biol 1995; 15:2600–11.PubMedGoogle Scholar
  13. 13.
    Harbour JW, Luo RX, Dei Santi A et al. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 1999; 98:859–69.PubMedGoogle Scholar
  14. 14.
    Lundberg AS, Weinberg RA. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol 1998; 18:753–61.PubMedGoogle Scholar
  15. 15.
    Ren S, Rollins BJ. Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell 2004; 117:239–51.PubMedGoogle Scholar
  16. 16.
    LaBaer J, Garrett MD, Stevenson LF et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev 1997; 11:847–62.PubMedGoogle Scholar
  17. 17.
    Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy and breast cancer. J Natl Cancer Inst 1998; 90:814–23.PubMedGoogle Scholar
  18. 18.
    Clarke CL, Sutherland RL. Progestin regulation of cellular proliferation. Endocr Rev 1990; 11:266–301.PubMedGoogle Scholar
  19. 19.
    De Vivo I, Hankinson SE, Colditz GA et al. A functional polymorphism in the progesterone receptor gene is associated with an increase in breast cancer risk. Cancer Res 2003; 63:5236–8.PubMedGoogle Scholar
  20. 20.
    Sutherland RL, Prall OW, Watts CK et al. Estrogen and progestin regulation of cell cycle progression. Journal of Mammary Gland Biology and Neoplasia 1998; 3:63–72.PubMedGoogle Scholar
  21. 21.
    Sutherland RL, Musgrove EA. Cyclins and breast cancer. J Mammary Gland Biol Neoplasia 2004; 9:95–104.PubMedGoogle Scholar
  22. 22.
    Hewitt SC, Harrell JC, Korach KS. Lessons in estrogen biology from knockout and transgenic animals. Annu Rev Physiol 2005; 67:285–308.PubMedGoogle Scholar
  23. 23.
    Ström A, Hartman J, Foster JS et al. Estrogen receptor beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proc Natl Acad Sci USA 2004; 101:1566–71.PubMedGoogle Scholar
  24. 24.
    Dubik D, Shiu RP. Transcriptional regulation of c-myc oncogene expression by estrogen in hormoneresponsive human breast cancer cells. J Biol Chem 1988; 263:12705–8.PubMedGoogle Scholar
  25. 25.
    Carroll JS, Swarbrick A, Musgrove EA et al. Mechanisms of growth arrest by c-myc antisense oligonucleotides in MCF-7 breast cancer cells: implications for the antiproliferative effects of antiestrogens. Cancer Res 2002; 62:3126–31.PubMedGoogle Scholar
  26. 26.
    Dubik D, Shiu RP. Mechanism of estrogen activation of c-myc oncogene expression. Oncogene 1992; 7:1587–94.PubMedGoogle Scholar
  27. 27.
    Carroll JS, CA M, JS et al. Genome-wide analysis of estrogen receptor binding sites. Nat Genet 2006; 38:1289–97.PubMedGoogle Scholar
  28. 28.
    Nass SJ, Dickson RB. Defining a role for c-Myc in breast tumorigenesis. Breast Cancer Research and Treatment 1997; 44:1–22.PubMedGoogle Scholar
  29. 29.
    Heikkila R, Schwab G, Wickstrom E et al. A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from G0 to G1. Nature 1987; 328:445–9.PubMedGoogle Scholar
  30. 30.
    Prall OWJ, Rogan EM, Musgrove EA et al. c-Myc or cyclin D1 mimics estrogen effects on cyclin E-cdk2 activation and cell cycle reentry. Mol Cell Biol 1998; 18:4499–508.PubMedGoogle Scholar
  31. 31.
    Dang CV. c-Myc target genes involved in cell growth, apoptosis and metabolism. Molecular and Cellular Biology 1999; 19:1–11.PubMedGoogle Scholar
  32. 32.
    Mukherjee S, Conrad SE. C-Myc suppresses p21 WAF1/CIP1 expression during estrogen signaling and antiestrogen resistance in human breast cancer cells. J Biol Chem 2005; 280:17617–25.PubMedGoogle Scholar
  33. 33.
    Prall OWJ, Sarcevic B, Musgrove EA et al. Estrogen-induced activation of cdk4 and cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-cdk2. J Biol Chem 1997; 272:10882–94.PubMedGoogle Scholar
  34. 34.
    Musgrove EA, Lee CS, Buckley MF et al. 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 1994; 91:8022–6.PubMedGoogle Scholar
  35. 35.
    Musgrove EA, Hamilton JA, Lee CS et al. 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; 13:3577–87.PubMedGoogle Scholar
  36. 36.
    Wilcken NR, Prall OW, Musgrove EA et al. Inducible overexpression of cyclin D1 in breast cancer cells reverses the growth-inhibitory effects of antiestrogens. Clin Cancer Res 1997; 3:849–54.PubMedGoogle Scholar
  37. 37.
    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. Molecular and Cellular Biology 1996; 16:6917–25.PubMedGoogle Scholar
  38. 38.
    Planas-Silva MD, Weinberg RA. Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Molecular and Cellular Biology 1997; 17:4059–69.PubMedGoogle Scholar
  39. 39.
    Prall OW, Carroll JS, Sutherland RL. A low abundance pool of nascent p21WAF1/Cip1 is targeted by estrogen to activate cyclin E*Cdk2. J Biol Chem 2001; 276:45433–42.PubMedGoogle Scholar
  40. 40.
    Foster JS, Fernando RI, Ishida N et al. Estrogens down-regulate p27Kip1 in breast cancer cells through Skp2 and through nuclear export mediated by the ERK pathway. J Biol Chem 2003; 278:41355–66.PubMedGoogle Scholar
  41. 41.
    Eeckhoute J, Carroll JS, Geistlinger TR et al. A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer. Genes Dev 2006; 20:2513–26.PubMedGoogle Scholar
  42. 42.
    Musgrove EA, Lee CS, Sutherland RL. Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor alpha, epidermal growth factor receptor, c-fos and c-myc genes. Mol Cell Biol 1991; 11:5032–43.PubMedGoogle Scholar
  43. 43.
    Swarbrick A, Lee CSL, Sutherland RL et al. Cooperation of p27Kipl and p18INK4c in progestin-mediated cell cycle arrest in T-47D breast cancer cells. Mol Cell Biol 2000; 20:2581–91.PubMedGoogle Scholar
  44. 44.
    Musgrove EA, Swarbrick A, Lee CS et al. Mechanisms of cyclin-dependent kinase inactivation by progestins. Mol Cell Biol 1998; 18:1812–25.PubMedGoogle Scholar
  45. 45.
    Caldon CE, Lee CS, Sutherland RL et al. Wilms’ tumor protein 1: an early target of progestin regulation in T-47D breast cancer cells that modulates proliferation and differentiation. Oncogene 2007; doi: 10.1038/sj.onc.1210622.Google Scholar
  46. 46.
    Stewart TA, Pattengale PK, Leder P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 1984; 38:627–37.PubMedGoogle Scholar
  47. 47.
    Jamerson MH, Johnson MD, Dickson RB. Of mice and myc: c-Myc and mammary tumorigenesis. J Mammary Gland Biol Neoplasia 2004; 9:27–37.PubMedGoogle Scholar
  48. 48.
    Wang TC, Cardiff RD, Zukerberg L et al. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 1994; 369:669–71.PubMedGoogle Scholar
  49. 49.
    Bortner DM, Rosenberg MP. Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. Mol Cell Biol 1997; 17:453–9.PubMedGoogle Scholar
  50. 50.
    Lee RJ, Albanese C, Fu M et al. Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol 2000; 20:672–83.PubMedGoogle Scholar
  51. 51.
    Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature 2001; 411:1017–21.PubMedGoogle Scholar
  52. 52.
    Serrano M, Gomez-Lahoz E, DePinho RA et al. Inhibition of ras-induced proliferation and cellular transformation by p16INK4. Science 1995; 267:249–52.PubMedGoogle Scholar
  53. 53.
    Yang C, Ionescu-Tiba V, Burns K et al. The role of the cyclin D1-dependent kinases in ErbB2-mediated breast cancer. Am J Pathol 2004; 164:1031–8.PubMedGoogle Scholar
  54. 54.
    Bowe DB, Kenney NJ, Adereth Y et al. Suppression of Neu-induced mammary tumor growth in cyclin D1 deficient mice is compensated for by cyclin E. Oncogene 2002; 21:291–8.PubMedGoogle Scholar
  55. 55.
    Geng Y, Whoriskey W, Park MY et al. Rescue of cyclin D1 deficiency by knockin cyclin E. Cell 1999; 97:767–77.PubMedGoogle Scholar
  56. 56.
    Yu Q, Sicinska E, Geng Y et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 2006; 9:23–32.PubMedGoogle Scholar
  57. 57.
    Landis MW, Pawlyk BS, Li T et al. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9:13–22.Google Scholar
  58. 58.
    Geng Y, Yu Q, Sicinska E et al. Cyclin E ablation in the mouse. Cell 2003; 114:431–43.PubMedGoogle Scholar
  59. 59.
    Robanus-Maandag EC, Bosch CA, Kristel PM et al. Association of C-MYC amplification with progression from the in situ to the invasive stage in C-MYC-amplified breast carcinomas. J Pathol 2003; 201:75–82.PubMedGoogle Scholar
  60. 60.
    Deming SL, Nass SJ, Dickson RB et al. C-myc amplification in breast cancer: a meta-analysis of its occurrence and prognostic relevance. Br J Cancer 2000; 83:1688–95.PubMedGoogle Scholar
  61. 61.
    Schlotter CM, Vogt U, Bosse U et al. C-myc, not HER-2/neu, can predict recurrence and mortality of patients with node-negative breast cancer. Breast Cancer Res 2003; 5:R30–6.PubMedGoogle Scholar
  62. 62.
    Naidu R, Wahab NA, Yadav M et al. Protein expression and molecular analysis of c-myc gene in primary breast carcinomas using immunohistochemistry and differential polymerase chain reaction. Int J Mol Med 2002; 9:189–96.PubMedGoogle Scholar
  63. 63.
    Blancato J, Singh B, Liu A et al. Correlation of amplification and overexpression of the c-myc oncogene in high-grade breast cancer: FISH, in situ hybridisation and immunohistochemical analyses. Br J Cancer 2004; 90:1612–9.PubMedGoogle Scholar
  64. 64.
    Callagy GM, Pharoah PD, Pinder SE et al. Bcl-2 is a prognostic marker in breast cancer independently of the Nottingham Prognostic Index. Clin Cancer Res 2006; 12:2468–75.PubMedGoogle Scholar
  65. 65.
    Alle KM, Henshall SM, Field AS et al. Cyclin D1 protein is overexpressed in hyperplasia and intraductal carcinoma of the breast. Clinical Cancer Research 1998; 4:847–54.PubMedGoogle Scholar
  66. 66.
    Buckley MF, Sweeney KJ, Hamilton JA et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene 1993; 8:2127–33.PubMedGoogle Scholar
  67. 67.
    Evron E, Umbricht CB, Korz D et al. Loss of cyclin D2 expression in the majority of breast cancers is associated with promoter hypermethylation. Cancer Research 2001; 61:2782–7.PubMedGoogle Scholar
  68. 68.
    Bartkova J, Zemanova M, Bartek J. Abundance and subcellular localisation of cyclin D3 in human tumours. International Journal of Cancer 1996; 65:323–7.Google Scholar
  69. 69.
    Wang L, Shao ZM. Cyclin E expression and prognosis in breast cancer patients: a meta-analysis of published studies. Cancer Invest 2006; 24:581–7.PubMedGoogle Scholar
  70. 70.
    Rudolph P, Kühling H, Alm P et al. Differential prognostic impact of the cyclins E and B in premenopausal and postmenopausal women with lymph node-negative breast cancer. International Journal of Cancer 2003; 105:674–80.Google Scholar
  71. 71.
    Keyomarsi K, O’Leary N, Molnar G et al. Cyclin E, a potential prognostic marker for breast cancer. Cancer Research 1994; 54:380–5.PubMedGoogle Scholar
  72. 72.
    Keyomarsi K, Tucker SL, Buchholz TA et al. Cyclin E and survival in patients with breast cancer. N Engl J Med 2002; 347:1566–75.PubMedGoogle Scholar
  73. 73.
    Wingate H, Zhang N, McGarhen MJ et al. The tumor-specific hyperactive forms of cyclin E are resistant to inhibition by p21 and p27. J Biol Chem 2005; 280:15148–57.PubMedGoogle Scholar
  74. 74.
    Spruck C, Sun D, Fiegl H et al. Detection of low molecular weight derivatives of cyclin E1 Is a function of cyclin E1 protein levels in breast cancer. Cancer Res 2006; 66:7355–60.PubMedGoogle Scholar
  75. 75.
    van’t Veer LJ, Dai H, van de Vijver MJ et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002; 415:530–6.Google Scholar
  76. 76.
    Wang Y, Klijn JG, Zhang Y et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 2005; 365:671–9.PubMedGoogle Scholar
  77. 77.
    Sotiriou C, Wirapati P, Loi S et al. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst 2006; 98:262–72.PubMedGoogle Scholar
  78. 78.
    Sieuwerts AM, Look MP, Meijer-van Gelder ME et al. Which cyclin E prevails as prognostic marker for breast cancer? Results from a retrospective study involving 635 lymph node-negative breast cancer patients. Clin Cancer Res 2006; 12:3319–28.PubMedGoogle Scholar
  79. 79.
    Desmedt C, Ouriaghli FE, Durbecq V et al. Impact of cyclins E, neutrophil elastase and proteinase 3 expression levels on clinical outcome in primary breast cancer patients. Int J Cancer 2006; 119:2539–45.PubMedGoogle Scholar
  80. 80.
    Alkarain A, Slingerland J. Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer. Breast Cancer Research 2004; 6:13–21.PubMedGoogle Scholar
  81. 81.
    Chen C, Seth AK, Aplin AE. Genetic and expression aberrations of E3 ubiquitin ligases in human breast cancer. Molecular Cancer Research 2006; 4:695–707.PubMedGoogle Scholar
  82. 82.
    Zheng W-Q, Zheng J-M, Ma R et al. Relationship between levels of Skp2 and p27 in breast carcinomas and possible role of Skp2 as targeted therapy. Steroids 2005; 70:770–4.PubMedGoogle Scholar
  83. 83.
    Alkarain A, Jordan R, Slingerland J. p27 deregulation in breast cancer: prognostic significance and implications for therapy. Journal of Mammary Gland Biology_& Neoplasia 2004; 9:67–80.Google Scholar
  84. 84.
    Tsutsui S, Inoue H, Yasuda K et al. Inactivation of PTEN is associated with a low p27Kip1 protein expression in breast carcinoma. Cancer 2005; 104:2048–53.PubMedGoogle Scholar
  85. 85.
    Wu FY, Wang SE, Sanders ME et al. Reduction of cytosolic p27Kip1 inhibits cancer cell motility, survival and tumorigenicity. Cancer Res 2006; 66:2162–72.PubMedGoogle Scholar
  86. 86.
    Tlsty TD, Crawford YG, Holst CR et al. Genetic and epigenetic changes in mammary epithelial cells may mimic early events in carcinogenesis. J Mammary Gland Biol Neoplasia 2004; 9:263–74.PubMedGoogle Scholar
  87. 87.
    Di Vinci A, Perdelli L, Banelli B et al. p16INK4a promoter methylation and protein expression in breast fibroadenoma and carcinoma. International Journal of Cancer 2005; 114:414–21.Google Scholar
  88. 88.
    Huschtscha LI, Noble JR, Neumann AA et al. Loss of p16INK4 expression by methylation is associated with lifespan extension of human mammary epithelial cells. Cancer Res 1998; 58:3508–12.PubMedGoogle Scholar
  89. 89.
    Dublin EA, Patel NK, Gillett CE et al. Retinoblastoma and p16 proteins in mammary carcinoma: Their relationship to cyclin D1 and histopathological parameters. International Journal of Cancer 1998; 79:71–5.Google Scholar
  90. 90.
    Hui R, Macmillan RD, Kenny FS et al. INK4a gene expression and methylation in primary breast cancer: overexpression of p16INK4a messenger RNA is a marker of poor prognosis. Clin Cancer Res 2000; 6:2777–87.PubMedGoogle Scholar
  91. 91.
    Emig R, Magener A, Ehemann V et al. Aberrant cytoplasmic expression of the p16 protein in breast cancer is associated with accelerated tumour proliferation, British Journal of Cancer 1998; 78:1661–8.PubMedGoogle Scholar
  92. 92.
    Jeng M-H, Shupnik MA, Bender TP et al. Estrogen receptor expression and function in long-term estrogen-deprived human breast cancer cells. Endocrinology 1998; 139:4164–74.PubMedGoogle Scholar
  93. 93.
    Venditti M, Iwasiow B, Orr FW et al. C-myc gene expression alone is sufficient to confer resistance to antiestrogen in human breast cancer cells. Int J Cancer 2002; 99:35–42.PubMedGoogle Scholar
  94. 94.
    Sears R, Lone G, DeGregori J et al. Ras enhances Myc protein stability. Molecular Cell 1999; 3:169–79.PubMedGoogle Scholar
  95. 95.
    Sears R, Nuckolls F, Haura E et al. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes and Development 2000; 14:2501–14.PubMedGoogle Scholar
  96. 96.
    Neve RM, Sutterluty H, Pullen N et al. Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells. Oncogene 2000; 19:1647–56.PubMedGoogle Scholar
  97. 97.
    Nass SJ, Dickson RB. Epidermal growth factor-dependent cell cycle progression is altered in mammary epithelial cells that overexpress c-myc. Clinical Cancer Research 1998; 4:1813–22.PubMedGoogle Scholar
  98. 98.
    Al-Kuraya K, Schraml P, Torhorst J et al. Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res 2004; 64:8534–40.PubMedGoogle Scholar
  99. 99.
    Berns EM, Foekens JA, van Staveren IL et al. Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene 1995; 159:11–8.PubMedGoogle Scholar
  100. 100.
    Pellikainen MJ, Pekola TT, Ropponen KM et al. p21WAF1 expression in invasive breast cancer and its association with p53, AP-2, cell proliferation and prognosis. J Clin Pathol 2003; 56:214–20.PubMedGoogle Scholar
  101. 101.
    Gohring UJ, Bersch A, Becker M et al. p21(waf) correlates with DNA replication but not with prognosis in invasive breast cancer. J Clin Pathol 2001; 54:866–70.PubMedGoogle Scholar
  102. 102.
    O’Hanlon DM, Kiely M, MacConmara M et al. An immunohistochemical study of p21 and p53 expression in primary node-positive breast carcinoma. Eur J Surg Oncol 2002; 28:103–7.PubMedGoogle Scholar
  103. 103.
    Caffo O, Doglioni C, Veronese S et al. Prognostic value of p21(WAF1) and p53 expression in breast carcinoma: an immunohistochemical study in 261 patients with long-term follow-up. Clin Cancer Res 1996; 2:1591–9.PubMedGoogle Scholar
  104. 104.
    Winters ZE, Leek RD, Bradburn MJ et al. Cytoplasmic p21WAF1/CIP1 expression is correlated with HER-2/ neu in breast cancer and is an independent predictor of prognosis. Breast Cancer Res 2003; 5:R242–9.PubMedGoogle Scholar
  105. 105.
    Kilker RL, Hartl MW, Rutherford TM et al. Cyclin D1 expression is dependent on estrogen receptor function in tamoxifen-resistant breast cancer cells. J Steroid Biochem Mol Biol 2004; 92:63–71.PubMedGoogle Scholar
  106. 106.
    Howell A, DeFriend D, Robertson J et al. Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer. Lancet 1995; 345:29–30.PubMedGoogle Scholar
  107. 107.
    Musgrove EA, Hunter L-JK, Lee CSL et al. Cyclin D1 overexpression induces progestin resistance in T47D breast cancer cells despite p27KIP1 association with cyclin E-cdk2. Journal of Biological Chemistry 2001; 275:47675–83.Google Scholar
  108. 108.
    Neuman E, Ladha MH, Lin N et al. Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Mol Cell Biol 1997; 17:5338–47.PubMedGoogle Scholar
  109. 109.
    Zwijsen RML, Wientjens E, Klompmaker R et al. CDK-independent activation of estrogen receptor by cyclin D1. Cell 1997; 88:405–15.PubMedGoogle Scholar
  110. 110.
    Dickson C, Fantl V, Gillett C et al. Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer. Cancer Lett 1995; 90:43–50.PubMedGoogle Scholar
  111. 111.
    Bieche I, Olivi M, Nogues C et al. Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays. British Journal of Cancer 2002; 86:580–6.PubMedGoogle Scholar
  112. 112.
    Kenny FS, Hui R, Musgrove EA et al. Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer. Clin Cancer Res 1999; 5:2069–76.PubMedGoogle Scholar
  113. 113.
    Stendahl M, Kronblad A, Ryden L et al. Cyclin D1 overexpression is a negative predictive factor for tamoxifen response in postmenopausal breast cancer patients. Br J Cancer 2004; 90:1942–8.PubMedGoogle Scholar
  114. 114.
    Han S, Park K, Bae BN et al. Cyclin D1 expression and patient outcome after tamoxifen therapy in estrogen receptor positive metastatic breast cancer. Oncol Rep 2003; 10:141–4.PubMedGoogle Scholar
  115. 115.
    Dhillon NK, Mudryj M. Ectopic expression of cyclin E in estrogen responsive cells abrogates antiestrogen mediated growth arrest. Oncogene 2002; 21:4626–34.PubMedGoogle Scholar
  116. 116.
    Hui R, Finney GL, Carroll JS et al. Constitutive overexpression of cyclin D1 but not cyclin E confers acute resistance to antiestrogens in T-47D breast cancer cells. Cancer Res 2002; 62:6916–23.PubMedGoogle Scholar
  117. 117.
    Akli S, Zheng PJ, Multani AS et al. Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27 and antiestrogens in breast cancer. Cancer Res 2004; 64:3198–208.PubMedGoogle Scholar
  118. 118.
    Bukholm IR, Bukholm G, Nesland JM. Over-expression of cyclin A is highly associated with early relapse and reduced survival in patients with primary breast carcinomas. Int J Cancer 2001; 93:283–7.PubMedGoogle Scholar
  119. 119.
    Span PN, Tjan-Heijnen VC, Manders P et al. Cyclin-E is a strong predictor of endocrine therapy failure in human breast cancer. Oncogene 2003; 22:4898–904.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  • Alison J. Butt
    • 2
  • C. Elizabeth Caldon
    • 2
  • Catriona M. McNeil
    • 2
  • Alexander Swarbrick
    • 2
  • Elizabeth A. Musgrove
    • 2
  • Robert L. Sutherland
    • 1
    • 2
  1. 1.Cancer Research ProgramGarvan Institute of Medical ResearchDarlinghurstAustralia
  2. 2.Cancer Research ProgramGarvan Institute of Medical ResearchDarlinghurstAustralia

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