Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of histone deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer cells and blocks tamoxifen-induced proliferation of uterine cells

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

Abstract

Here we report a novel potential therapeutic strategy using histone deacetylase (HDAC) inhibitors to enhance the action of hormonal therapy agents in estrogen receptor alpha (ERα)-positive breast cancer. HDAC inhibitors [trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA)], inhibited proliferation of MCF-7 breast cancer cells and, in combination with tamoxifen inhibited proliferation better than with either agent alone. VPA, an anti-convulsant drug with HDAC inhibitory activity, enhanced tamoxifen action at doses within the concentration range used for anti-convulsive therapy. VPA cooperated with tamoxifen in a variety of ERα-positive cell lines and was also effective when combined with other antiestrogens, and with aromatase inhibition. VPA enhanced antiestrogen action by promoting cell death via apoptosis without affecting cell cycling. Some of this action may be due to VPA’s ability to induce the pro-apoptotic gene Bik, which is also induced by antiestrogens. Remarkably, VPA blocked the undesirable pro-proliferative action of tamoxifen on uterine endometrial cells. Our in vitro results suggest that VPA and other HDAC inhibitors have the potential to enhance hormonal therapy for ERα-positive breast cancer and simultaneously reverse the adverse effects of antiestrogens in the uterus.

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 (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Clarke R, Skaar TC, Bouker KB et al (2001) Molecular and pharmacological aspects of antiestrogen resistance. J Steroid Biochem Mol Biol 76(1–5):71–84

    Article  PubMed  CAS  Google Scholar 

  2. Osborne CK (1998) Tamoxifen in the treatment of breast cancer. N Engl J Med 339(22):1609–1618

    Article  PubMed  CAS  Google Scholar 

  3. Ring A, Dowsett M (2004) Mechanisms of tamoxifen resistance. Endocr Relat Cancer 11(4):643–658

    Article  PubMed  CAS  Google Scholar 

  4. Fisher B, Costantino JP, Redmond CK et al (1994) Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86(7):527–537

    Article  PubMed  CAS  Google Scholar 

  5. Gelber RD, Cole BF, Goldhirsch A et al (1996) Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: meta-analysis of quality-adjusted survival. Lancet 347(9008):1066–1071

    Article  PubMed  CAS  Google Scholar 

  6. Rivkin SE, Green S, Metch B et al (1994) Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study. J Clin Oncol 12(10):2078–2085

    PubMed  CAS  Google Scholar 

  7. Woods KE, Randolph JK Gewirtz DA (1994) Antagonism between tamoxifen and doxorubicin in the MCF-7 human breast tumor cell line. Biochem Pharmacol 47(8):1449–1452

    Article  PubMed  CAS  Google Scholar 

  8. De Soto JA, Bowen D, Davis JH et al (2002) Sequence- and time-dependent antagonism between raloxifene and methotrexate in human breast cancer cells. Anticancer Res 22(2A):1007–1009

    PubMed  Google Scholar 

  9. Osborne CK, Kitten L, Arteaga CL (1989) Antagonism of chemotherapy-induced cytotoxicity for human breast cancer cells by antiestrogens. J Clin Oncol 7(6):710–717

    PubMed  CAS  Google Scholar 

  10. Johnston SR (2006) Clinical efforts to combine endocrine agents with targeted therapies against epidermal growth factor receptor/human epidermal growth factor receptor 2 and mammalian target of rapamycin in breast cancer. Clin Cancer Res 12(3 Pt 2):1061s–1068s

    Article  PubMed  CAS  Google Scholar 

  11. Wyeth Pharmaceuticals (2006) Termination of phase 3 clinical program with oral temsirolimus in women with metastatic breast cancer. From: Medical News Today http://www.medicalnewstoday.com/medicalnews.php?newsid=39843. Cited 21 Mar 2006

  12. Jang ER, Lim SJ, Lee ES et al (2004) The histone deacetylase inhibitor trichostatin A sensitizes estrogen receptor alpha-negative breast cancer cells to tamoxifen. Oncogene 23(9):1724–1736

    Article  PubMed  CAS  Google Scholar 

  13. Jansen MS, Nagel SC, Miranda PJ et al (2004) Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci USA 101(18):7199–7204

    Article  PubMed  CAS  Google Scholar 

  14. Margueron R, Duong V, Bonnet S et al (2004) Histone deacetylase inhibition and estrogen receptor alpha levels modulate the transcriptional activity of partial antiestrogens. J Mol Endocrinol 32(2):583–594

    Article  PubMed  CAS  Google Scholar 

  15. Villar-Garea A, Esteller M (2004) Histone deacetylase inhibitors: understanding a new wave of anticancer agents. Int J Cancer 112(2):171–178

    Article  PubMed  CAS  Google Scholar 

  16. Marks P, Rifkind RA, Richon VM et al (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1(3):194–202

    Article  PubMed  CAS  Google Scholar 

  17. Glaser KB, Staver MJ, Waring JF et al (2003) Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2(2):151–163

    PubMed  CAS  Google Scholar 

  18. Richon VM, Sandhoff TW, Rifkind RA et al (2000) Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA 97(18):10014–10019

    Article  PubMed  CAS  Google Scholar 

  19. Munster PN, Troso-Sandoval T, Rosen N et al (2001) The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res 61(23):8492–8497

    PubMed  CAS  Google Scholar 

  20. Kim MS, Blake M, Baek JH et al (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63(21):7291–7300

    PubMed  CAS  Google Scholar 

  21. Castro-Galache MD, Ferragut JA, Barbera VM et al (2003) Susceptibility of multidrug resistance tumor cells to apoptosis induction by histone deacetylase inhibitors. Int J Cancer 104(5):579–586

    Article  PubMed  CAS  Google Scholar 

  22. Vigushin DM, Ali S, Pace PE et al (2001) Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin Cancer Res 7(4):971–976

    PubMed  CAS  Google Scholar 

  23. Margueron R, Licznar A, Lazennec G et al (2003) Oestrogen receptor alpha increases p21(WAF1/CIP1) gene expression and the antiproliferative activity of histone deacetylase inhibitors in human breast cancer cells. J Endocrinol 179(1):41–53

    Article  PubMed  CAS  Google Scholar 

  24. Reid G, Metivier R, Lin CY et al (2005) Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor alpha, in response to deacetylase inhibition by valproic acid and trichostatin A. Oncogene 24(31):4894–4907

    Article  PubMed  CAS  Google Scholar 

  25. Alao JP, Lam EW, Ali S et al (2004) Histone deacetylase inhibitor trichostatin A represses estrogen receptor alpha-dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines. Clin Cancer Res 10(23):8094–8104

    Article  PubMed  CAS  Google Scholar 

  26. Phiel CJ, Zhang F, Huang EY et al (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276(39):36734–36741

    Article  PubMed  CAS  Google Scholar 

  27. Gottlicher M, Minucci S, Zhu P et al (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. Embo J 20(24):6969–6978

    Article  PubMed  CAS  Google Scholar 

  28. Blaheta RA, Michaelis M, Driever PH et al (2005) Evolving anticancer drug valproic acid: insights into the mechanism and clinical studies. Med Res Rev 25(4):383–397

    Article  PubMed  CAS  Google Scholar 

  29. Olsen CM, Meussen-Elholm ET, Roste LS et al (2004) Antiepileptic drugs inhibit cell growth in the human breast cancer cell line MCF7. Mol Cell Endocrinol 213(2):173–179

    Article  PubMed  CAS  Google Scholar 

  30. Marchion DC, Bicaku E, Daud AI et al (2005) In vivo synergy between topoisomerase II and histone deacetylase inhibitors: predictive correlates. Mol Cancer Ther 4(12):1993–2000

    Article  PubMed  CAS  Google Scholar 

  31. Munster PN, Minton SE, Marchion DC, Carter W, Bicaku E, Padilla B, Lush R, Sullivan DM, Daud AI (2006) Phase I/II trial and pharmacokinetic/pharmacodynamic analysis exploring a synergistic interaction between the histone deacetylase inhibitor, valpoic acid and the anthracycline, epirubicin. Presented at the San Antonio Breast Cancer Symposium, San Antonio, TX

  32. Liu MM, Albanese C, Anderson CM et al (2002) Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. J Biol Chem 277(27):24353–24360

    Article  PubMed  CAS  Google Scholar 

  33. Webb P, Nguyen P, Valentine C et al (1999) The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol Endocrinol 13(10):1672–1685

    Article  PubMed  CAS  Google Scholar 

  34. Vermes I, Haanen C, Steffens-Nakken H et al (1995) A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods 184(1):39–51

    Article  PubMed  CAS  Google Scholar 

  35. Webb P, Nguyen P, Kushner PJ (2003) Differential SERM effects on corepressor binding dictate ERalpha activity in vivo. J Biol Chem 278(9):6912–6920

    Article  PubMed  CAS  Google Scholar 

  36. Hur J, Chesnes J, Coser KR et al (2004) The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis. Proc Natl Acad Sci USA 101(8):2351–2356

    Article  PubMed  CAS  Google Scholar 

  37. Larionov AA, Berstein LM, Miller WR (2002) Local uptake and synthesis of oestrone in normal and malignant postmenopausal breast tissues. J Steroid Biochem Mol Biol 81(1):57–64

    Article  PubMed  CAS  Google Scholar 

  38. Benz CC, Scott GK, Sarup JC et al (1993) Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 24(2):85–95

    Article  CAS  Google Scholar 

  39. Kurokawa H, Lenferink AE, Simpson JF et al (2000) Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res 60(20):5887–5894

    PubMed  CAS  Google Scholar 

  40. Kato S (2001) Estrogen receptor-mediated cross-talk with growth factor signaling pathways. Breast Cancer 8(1):3–9

    Article  PubMed  CAS  Google Scholar 

  41. Lopez GN, Turck CW, Schaufele F et al (2001) Growth factors signal to steroid receptors through mitogen-activated protein kinase regulation of p160 coactivator activity. J Biol Chem 276(25):22177–22182

    Article  PubMed  CAS  Google Scholar 

  42. Bunone G, Briand PA, Miksicek RJ et al (1996) Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. Embo J 15(9):2174–2183

    PubMed  CAS  Google Scholar 

  43. Nicholson RI, Hutcheson IR, Harper ME et al (2002) Modulation of epidermal growth factor receptor in endocrine-resistant, estrogen-receptor-positive breast cancer. Ann N Y Acad Sci 963:104–115

    Article  PubMed  CAS  Google Scholar 

  44. Osborne CK, Schiff R (2003) Growth factor receptor cross-talk with estrogen receptor as a mechanism for tamoxifen resistance in breast cancer. Breast 12(6):362–367

    Article  PubMed  Google Scholar 

  45. Shou J, Massarweh S, Osborne CK et al (2004) Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96(12):926–935

    Article  PubMed  CAS  Google Scholar 

  46. Greco WR, Faessel H, Levasseur L (1996) The search for cytotoxic synergy between anticancer agents: a case of Dorothy and the ruby slippers? J Natl Cancer Inst 88(11):699–700

    Article  PubMed  CAS  Google Scholar 

  47. Isojarvi JI, Tauboll E, Herzog AG (2005) Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy. CNS Drugs 19(3):207–223

    Article  PubMed  Google Scholar 

  48. O’Donovan C, Kusumakar V, Graves GR et al (2002) Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder. J Clin Psychiatry 63(4):322–330

    PubMed  CAS  Google Scholar 

  49. Perucca E (2005) Birth defects after prenatal exposure to antiepileptic drugs. Lancet Neurol 4(11):781–786

    Article  PubMed  CAS  Google Scholar 

  50. Takai N, Desmond JC, Kumagai T et al (2004) Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells. Clin Cancer Res 10(3):1141–1149

    Article  PubMed  CAS  Google Scholar 

  51. Graziani G, Tentori L, Portarena I et al (2003) Valproic acid increases the stimulatory effect of estrogens on proliferation of human endometrial adenocarcinoma cells. Endocrinology 144(7):2822–2828

    Article  PubMed  CAS  Google Scholar 

  52. Nishida M, Kasahara K, Oki A et al (1996) Establishment of eighteen clones of Ishikawa cells. Hum Cell 9(2):109–116

    PubMed  CAS  Google Scholar 

  53. Gunin AG, Kapitova IN, Suslonova NV (2005) Effects of histone deacetylase inhibitors on estradiol-induced proliferation and hyperplasia formation in the mouse uterus. J Endocrinol 185(3):539–549

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would particularly like to thank Dr. Fred Schaufele for the careful reading of this manuscript and thoughtful suggestions. We also thank Marianna Zavodoskaya, Paul Webb, John Baxter, Michael Campbell, Ira Goldfine, and Jack Youngren for helpful discussions. Financial support was provided by the National Cancer Institute, NIH R01 CA 80210 (PJK) and the California Breast Cancer Research Project, 10FB-0046 (LHG). Peter Kushner has significant financial interests in, and is a former Director and Consultant to, Karobio AB a biotech company that develops ligands for nuclear receptors.

Author information

Authors and Affiliations

  1. Department of Medicine, University of California, P. O. Box 1640, San Francisco, CA , 94143, USA

    Leslie Hodges-Gallagher, Cathleen D. Valentine, Suzy El Bader & Peter J. Kushner

Authors
  1. Leslie Hodges-Gallagher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cathleen D. Valentine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suzy El Bader
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter J. Kushner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter J. Kushner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hodges-Gallagher, L., Valentine, C.D., Bader, S.E. et al. Inhibition of histone deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer cells and blocks tamoxifen-induced proliferation of uterine cells. Breast Cancer Res Treat 105, 297–309 (2007). https://doi.org/10.1007/s10549-006-9459-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-006-9459-6

Keywords

Search

Navigation

-