SpringerLink
Log in

Inhibition of Human Breast Cancer Cell Growth by Blockade of the Mevalonate-Protein Prenylation Pathway is not Prevented by Overexpression of Cyclin D1

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

Abstract

Overexpression of the cyclin D1 (CCND1) gene, encoding a downstream effector of mitogenic signals that plays a central role in G1 phase progression, is often found in cancerous cells. In sporadic breast cancer (BC), this is one of the most frequent and early genetic lesions identified so far, found in more than 50% of the tumors. Inhibitors of the mevalonate/protein prenylation pathway belong to a new family of cancer therapeutic agents that act by blocking intracellular mitogenic signal transduction pathways, thereby preventing expansion of pre-cancerous foci and inhibiting growth of transformed cells. It is not known at present whether constitutively high intracellular levels of cyclin D1 might interfere with the cytostatic actions of mevalonate/protein prenylation inhibitors. This possibility was investigated here by assessing the cell cycle effects of Simvastatin, a non-toxic upstream inhibitor of the mevalonate pathway, on human BC MCF-7 cells expressing either normal or enhanced levels of cyclin D1 from of a stably transfected, tet-inducible expression vector. Results show that constitutive overexpression of this protein, such as that found in sporadic BCs, does not influence the growth inhibitory effects of Simvastatin in vitro. In addition, D1-overexpressing embryo fibroblasts were also found to be responsive to the cell cycle effects of mevalonate/protein prenylation pathway blockade, further suggesting that high intracellular levels of cyclin D1 do not prevent the cytostatic actions of compounds targeting this metabolic pathway.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Thailand)

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Buchwald H: Cholesterol inhibition, cancer, and chemotherapy. Lancet 340: 127-128, 1992

    Google Scholar 

  2. Lowy DR, Willumsen BM: Rational cancer therapy. Nat Med 1: 747-748, 1995

    Google Scholar 

  3. Gibbs JB, Oliff A: The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Annu Rev Pharmacol Toxicol 37: 143-166, 1997

    Google Scholar 

  4. Omer CA, Kohl NE: CA1A2X-competitive inhibitors of farnesyltransferase as anticancer agents. Trends Parmacol Sci 18: 437-444, 1997

    Google Scholar 

  5. Lobell RB, Kohl NE: Pre-clinical development of farnesyltransferase inhibitors. Cancer Metastasis Rev 17: 203-210, 1998

    Google Scholar 

  6. Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature 343: 425-430, 1990

    Google Scholar 

  7. Gibbs JB, Oliff A, Kohl NE: Farnesyltransferase inhibitors: Ras research yields a potential anticancer therapeutic. Cell 77: 175-178, 1994

    Google Scholar 

  8. Gelb MH: Protein prenylation, et cetera: Signal transduction in two dimensions. Science 275: 1750-1751, 1997

    Google Scholar 

  9. Keyomarsi K, Sandoval L, Band V, Pardee AB: Synchronization of tumor and normal cells from multiple cell cycles by Lovastatin. Cancer Res 51: 3602-3609, 1991

    Google Scholar 

  10. Larsson O: Effects of isoprenoids on growth of normal human mammary epithelial cells and breast cancer cells in vitro. Anticancer Res 14: 123-128, 1994

    Google Scholar 

  11. Bonapace IM, Addeo R, Altucci L, Cicatiello L, Bifulco M, Laezza C, Salzano S, Sica V, Bresciani F, Weisz A: 17?-estradiol overcomes a G1 block induced by HMG-CoA reductase inhibitors and fosters cell cycle progression without inducing ERK-1 and-2 MAP kinase activation. Oncogene 12: 753-763, 1996

    Google Scholar 

  12. Inano H, Suzuki K, Onoda M, Wakabayashi K: Anticarcinogenic activity of simvastat in during the promotion phase of radiation-induced mammary tumorigenesis of rats. Carcinogenesis 18: 1723-1727, 1997

    Google Scholar 

  13. Alonso DF, Farina HG, Skilton G, Gabri MR, De Lorenzo MS, Gomez DE: Reduction of mammary tumor formation and metastasis by lovastatin, an inhibitor of the mevalonate pathway of cholesterol synthesis. Breast Cancer Res Treat 50: 83-93, 1998

    Google Scholar 

  14. Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P, Malkowski M, Ferrari E, Nielsen L, Prioloi N, Dell J, Sinha D, Syed J, Korfmaker WA, Nomeir AA, Lin CC, Wang L, Taveras AG, Doll RJ, Njoroge FG, Mallams AK, Remiszewski S, Catino JJ, Girijavallabhan VM, Kirshmeier P, Bishop WR: Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res 58: 4947-4956, 1998

    Google Scholar 

  15. Mangues R, Corral T, Kohl NE, Symmans WF, Lu S, Malumbres M, Gibbs JB, Oliffs A, Pellicer A: Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice. Cancer Res 58: 1253-1259, 1998

    Google Scholar 

  16. Kohl NE, Omer CA, Conner MW, Anthony NJ, Davede JP, Desolms SJ, Giuliani EA, Gomez RP, Graham SL, Hamilton K, Handt LK, Hartman GD, Koblan KS, Kral AM, Miller PJ, Mosser SD, O'Neill TJ, Rands E, Schaber MD, Gibbs JB, Oliff, A: Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med 1: 792-797, 1995

    Google Scholar 

  17. Norgaard P, Law B, Joseph H, Page DL, Shyr Y, Mays D, Pietenpol JA, Kohl NE, Oliff A, Coffrey RJ, Jr, Poulsen HS, Moses HL: Treatment with farnesyl-protein transferase inhibitor induces regression of mammary tumors in transforming growth factor (TGF) alpha and TGF alpha/neu transgenic mice by inhibition of mitogenic activity and induction of apoptosis. Clin Cancer Res 5: 35-42, 1999

    Google Scholar 

  18. Jones KD, Couldwell WT, Hinton DR, Su Y, He S, Anker L, Law RE: Lovastatin induces growth inhibition and apoptosis in human malignant glioblastoma cells. Biochem Biophys Res Commun 205: 1681-1687, 1994

    Google Scholar 

  19. Ghosh PM, Mott GE, Ghosh-Choudhury N, Radnik RA, Stapleton ML, Ghidoni JJ, Kreisberg JI: Lovastat in induces apoptosis by inhibiting mitotic and post-mitotic events in cultured mesangial cells. Biochim Biophys Acta 1359: 13-24, 1997

    Google Scholar 

  20. Lebowitz PF, Sakamuro D, Prendergast GC: Farnesyl transferase inhibitors induce apoptosis of ras-transformed cells denied substratum attachement. Cancer Res 57: 708-713, 1997

    Google Scholar 

  21. Vitale M, Di Matola T, Rossi G, Laezza C, Fenzi G, Bifulco M: Prenyltransferase inhibitors induce apoptosis in proliferating thyroid cells through a p53-independent CrmAsensitive, and caspase-3-like protease-dependent mechanism. Endocrinology 140: 698-704, 1999

    Google Scholar 

  22. Sherr CJ: Cancer cell cycles. Science 274: 1072-1077, 1996

    Google Scholar 

  23. Michalides RJAM, Hageman P, van Tinteren H, Houben L, Wietjens 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 

  24. Barnes DM, Gillet CE: Cyclin D1 in breast cancer. Breast Cancer Res Treat 52: 1-15, 1998

    Google Scholar 

  25. Steeg PS, Zhou Q. Cyclins and breast cancer. Breast Cancer Res Treat 52: 17-28, 1998

    Google Scholar 

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

    Google Scholar 

  27. Hall M, Peters G: Genetic alterations of cyclins, cyclindependent kinases, and cdk inhibitors in human cancer. In: Vande Woude GF, Klein G (eds) Advances in Cancer Research, Vol. 68. Academic Press, San Diego, 1996, pp 67-108

    Google Scholar 

  28. Zwijsen RML, Klompmaker R, Kristell PMP, van der Burg B, Michalides RJAM: Cyclin D1 triggers autonomous growth of breast cancer cells by governing cell cycle exit. Mol Cell Biol 16: 2554-2560, 1996

    Google Scholar 

  29. Pacilio C, Germano D, Addeo R, Altucci L, Belsito Petrizzi V, Cancemi M, Cicatiello L, Salzano S, Lallemand F, Michalides RJAM, Bresciani F, Weisz A: Constitutive overexpression of cyclin D1 does not prevent inhibition of hormone-responsive human breast cancer cell growth by antiestrogens. Cancer Res 58: 871-876, 1998

    Google Scholar 

  30. Jiang W, Kahn SM, Zhou P, Zhang YJ, 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 

  31. Altucci L, Addeo R, Cicatiello L, Dauvois S, Parker MG, Truss M, Beato M, Sica V, Bresciani F, Weisz A: 17?-estradiol induces cycl in D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G1-arrested human breast cancer cells. Oncogene 12: 2315-2324, 1996

    Google Scholar 

  32. Kitagawa M, Higashi H, Jung H-K, Suzuki-Takahashi I, Ikeda M, Tamai K, Kato JY, Segawa K, Yoshida E, Nishimura S, Taya Y: The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. EMBO J 15: 7060-7069, 1996

    Google Scholar 

  33. Weisz A, Cicatiello L, Persico E, Scalona M, Bresciani F: Estrogen stimulates transcription of c-jun protooncogene. Mol Endocrinol 4: 1041-1050, 1990

    Google Scholar 

  34. Seiler-Tuyns A, Birnstiel ML: Structure and expression in Lcells of a cloned H4 histone gene of the mouse. J Mol Biol 151: 607-625, 1981

    Google Scholar 

  35. Masiakowski P, Breathnach R, Bloch J, Gannon F, Krust A, Chambon P: Cloning of cDNA sequences of hormoneregulated genes from theMCF-7 human breast cancer cell line. Nucleic Acids Res 10: 7895-7903, 1982

    Google Scholar 

  36. Gray-Bablin J, Rao S, Keiomarsi K: Lovastatin induction of cyclin-dependent kinase inhibitors in human breast cancer cells occurs in a cell cycle-independent fashion. Cancer Res 57: 604-609, 1997

    Google Scholar 

  37. Lee SJ, Ha MJ, Nguyen P, Choi YH, Pirnia F, Kang WK, Wang XF, Kim SJ, Treppel JB: Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway induces p53-independenttranscriptional regulation of p21 (WAF1/CIP1) in human prostate carcinoma cells. J Biol Chem 273: 10618-10623, 1998

    Google Scholar 

  38. Rao S, Lowe M, Herliczek TW, Keyomarsi K: Lovastat in mediated G1 arrest in normal and tumor breast cells in through inhibition of CDK2 activity and redistribution of p21 and p27, independent of p53. Oncogene 17: 2393-2402, 1998

    Google Scholar 

  39. Sherr CJ, Roberts JM: Inhibitors of mammalian G1 cyclindependent kinases. Genes Dev 9: 1149-1163, 1995

    Google Scholar 

  40. Zwijsen RML, Wientjens EBHGM, Klompmaker R, van der Sman J, Bernards R, Michalides RJAM: Cdk-independent activation of estrogen receptor by cyclin D1. Cell 88: 405-415, 1997

    Google Scholar 

  41. Altucci L, Addeo R, Cicatiello L, Germano D, Pacilio C, Battisat T, cancemi M, Belsito Petrizzi V, Bresciani F, Weisz A: Estrogen induce early and timed activation of cyclindependent kinases 4, 5 and 6 and increases cyclin messenger ribonucleic acid expression in rat uterus. Endocrinology 138: 978-984, 1997

    Google Scholar 

  42. Musgrove EA, Lee CSL, Buckley MF, Sutherland RL: Cycl in D1 induction in breast cancer cells shortens G1 and is suffi-cient for cells arrested in G1 to complete the cell cycle. Proc Natl Acad Sci USA 91: 8022-8026, 1994

    Google Scholar 

  43. Musgrove EA, Sarcevic B, Sutherland RL: 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, 1996

    Google Scholar 

  44. Rayson D, Erlichman C, Suman VJ, Roche PC, Wold, LE, Ingle JN, Donohue JH: Molecular markers in male breast carcinoma. Cancer 83: 1947-1955, 1998

    Google Scholar 

  45. Oyama T, Kashiwabara K, Yoshimoto K, Arnold A, Koerner F: Frequent overexpression of the cyclin D1 oncogene in invasive lobular carcinoma of the breast. Cancer Res 58: 2876-2880, 1998

    Google Scholar 

  46. Shesadri R, Lee CS, Hui R, McCaul K, Horsfall DJ, Sutherland RL: Cycl in 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 

  47. Collecchi P, Passoni A, Rocchetta M, Gnesi E, Baldini E, Bevilacqua G: Cyclin-D1 expression in node-positive (N+) and node-negative (N-) infiltrating human mammary carcinomas. Int J Cancer 84, 139-144, 1999

    Google Scholar 

  48. 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 

  49. Vogt A, Sun J, Qian Y, Hamilton AD, Sebti SM: The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21WAF1/CIP1/SDI1 in a p53-independent manner. J Biol Chem 272: 27224-27229, 1997

    Google Scholar 

  50. Geng Y, Whoriskey W, Park MY, Bronson RT, Medema RH, Li T, Weinberg RA: Rescue of cyclin D1 deficiency by knockin cyclin E. Cell 97: 767-777, 1999

    Google Scholar 

  51. 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 

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

    Google Scholar 

  53. 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 

  54. Larsson O, Blegen H: Regulatory role of mevalonate in the growth of normal and neoplastic human mammary epithelial cells. Anticancer Res 13: 1075-1079, 1993

    Google Scholar 

  55. Planas-Silva MD, Weinberg RA: Estrogen-dependent cyclin E-Cdk2 activation through p21 redistribution. Mol Cell Biol 17: 4059-4069, 1997

    Google Scholar 

  56. Prall OWJ, Sarcevic B, Musgrove E, Watts CKW, Sutherland RL: Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cycl in D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem 272: 10882-10894, 1997

    Google Scholar 

  57. Prall OWJ, Rogan EM, Musgrove E, Watts CKW, Sutherland RL: c-myc or cyclin D1 mimics estrogen effects on cyclin E-Cdk2 activation and cell cycle reentry. Mol Cell Biol 18: 4499-4508, 1998

    Google Scholar 

  58. Cheng M, Sexl V, Sherr CJ, Roussel MF: Assembly of cycl in D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase (MEK1). Proc Natl Acad Sci USA 95: 1091-1096, 1998

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Istituto di Patologia Generale e Oncologia, Facoltà di Medicina e Chirurgia, Seconda Università di Napoli, Naples, Italy

    Domenico Germano, Carmen Pacilio, Massimo Cancemi, Luigi Cicatiello, Lucia Altucci, Valeria Belsito Petrizzi, Carmine Sperandio, Francesco Bresciani & Alessandro Weisz

  2. Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche/Dipartimento di Biologia e Patologia Cellulare e Molecolare ‘L. Califano’, Università ‘Federico II’, Naples, Italy

    Salvatore Salzano

  3. Department of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Rob J.A.M. Michalides

  4. Biology Division, National Cancer Center Research Institute, Tokyo, Japan

    Yoichi Taya

Authors
  1. Domenico Germano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carmen Pacilio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Massimo Cancemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luigi Cicatiello
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lucia Altucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Valeria Belsito Petrizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carmine Sperandio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Salvatore Salzano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rob J.A.M. Michalides
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoichi Taya
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Francesco Bresciani
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Alessandro Weisz
    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

Germano, D., Pacilio, C., Cancemi, M. et al. Inhibition of Human Breast Cancer Cell Growth by Blockade of the Mevalonate-Protein Prenylation Pathway is not Prevented by Overexpression of Cyclin D1. Breast Cancer Res Treat 67, 23–33 (2001). https://doi.org/10.1023/A:1010675310188

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1010675310188

Search

Navigation