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The pan-DAC inhibitor LBH589 is a multi-functional agent in breast cancer cells: cytotoxic drug and inducer of sodium-iodide symporter (NIS)

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Abstract

New drugs with anti-tumor activity, also able to modify the expression of selected molecules, are under evaluation in breast cancer which is becoming resistant to conventional treatment, or in metastatic disease. The sodium-iodide symporter (NIS), which mediates iodide uptake into thyroid cells, and is the molecular basis of radioiodine imaging and therapy in thyroid cancer, is also expressed in a large portion of breast tumors. Since NIS expression in breast cancer is not sufficient for a significant iodide uptake, drugs able to induce its expression and correct function are under evaluation. In the present study, we report for the first time that the pan-deacetylase (DAC) inhibitor LBH589 (panobinostat) significantly induced NIS, both as mRNA and as protein, through the increase of NIS promoter activity, with the final consequence of obtaining a significant up-take of iodide in MCF7, T47D, and MDA-MB231 breast cancer cells. Moreover, we observed that LBH589 causes a significant reduction in cell viability of estrogen-sensitive and -insensitive breast cancer cells within nanomolar range. The anti-tumor effect of LBH589 is sustained by apoptosis induction and cell cycle arrest in G2/M. In conclusion, our data suggest that LBH589 might be a powerful tool in the management of breast cancer due to its multiple effects and support a potential application of LBH589 in the diagnosis and treatment of this disease.

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References

  1. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108

    Article  PubMed  Google Scholar 

  2. Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ, Cancer Intervention and Surveillance Modeling Network (CISNET) Collaborators (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353:1784–1792

    Article  CAS  PubMed  Google Scholar 

  3. Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN (2007) Overview of resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol 608:1–22

    Article  CAS  PubMed  Google Scholar 

  4. Cardoso F, Bedard PL, Winer EP, Pagani O, Senkus-Konefka E, Fallowfield LJ, Kyriakides S, Costa A, Cufer T, Albain KS, ESO-MBC Task Force (2009) International guidelines for management of metastatic breast cancer: combination vs sequential single-agent chemotherapy. J Natl Cancer Inst 101:1174–1181

    Article  CAS  PubMed  Google Scholar 

  5. Dai G, Levy O, Carrasco N (1996) Cloning and characterization of the thyroid iodide transporter. Nature 379:458–460

    Article  CAS  PubMed  Google Scholar 

  6. Reiners C, Dietlein M, Luster M (2008) Radio-iodine therapy in differentiated thyroid cancer: indications and procedures. Best Pract Res Clin Endocrinol Metab 22:989–1007

    Article  CAS  PubMed  Google Scholar 

  7. Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, Deng HF, Amenta PS, Fineberg S, Pestell RC, Carrasco N (2000) The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nat Med 6:871–878

    Article  CAS  PubMed  Google Scholar 

  8. Wapnir IL, van de Rijn M, Nowels K, Amenta PS, Walton K, Montgomery K, Greco RS, Dohán O, Carrasco N (2003) Immunohistochemical profile of the sodium/iodide symporter in thyroid, breast, and other carcinomas using high density tissue microarrays and conventional sections. J Clin Endocrinol Metab 88:1880–1888

    Article  CAS  PubMed  Google Scholar 

  9. Wapnir IL, Goris M, Yudd A, Dohan O, Adelman D, Nowels K, Carrasco N (2004) The Na+/I− symporter mediates iodide uptake in breast cancer metastases and can be selectively down-regulated in the thyroid. Clin Cancer Res 10:4294–4302

    Article  CAS  PubMed  Google Scholar 

  10. Moon DH, Lee SJ, Park KY, Park KK, Ahn SH, Pai MS, Chang H, Lee HK, Ahn IM (2001) Correlation between 99mTc pertechnetate uptakes and expressions of human sodium iodide symporter gene in breast tumor tissues. Nucl Med Biol 28:829–834

    Article  CAS  PubMed  Google Scholar 

  11. Boelaert K, Franklyn JA (2003) Sodium iodide symporter: a novel strategy to target breast, prostate, and other cancers? Lancet 361:796–797

    Article  CAS  PubMed  Google Scholar 

  12. Kogai T, Kanamoto Y, Li AI, Che LH, Ohashi E, Taki K, Chandraratna RA, Saito T, Brent GA (2005) Differential regulation of sodium/iodide symporter gene expression by nuclear receptor ligands in MCF-7 breast cancer cells. Endocrinology 146:3059–3069

    Article  CAS  PubMed  Google Scholar 

  13. Willhauck MJ, Sharif-Samani B, Senekowitsch-Schmidtke R, Wunderlich N, Göke B, Morris JC, Spitzweg C (2008) Functional sodium iodide symporter expression in breast cancer xenografts in vivo after systemic treatment with retinoic acid and dexamethasone. Breast Cancer Res Treat 109:263–272

    Article  CAS  PubMed  Google Scholar 

  14. Ohashi E, Kogai T, Kagechika H, Brent GA (2009) Activation of the PI3 kinase pathway by retinoic acid mediates sodium/iodide symporter induction and iodide transport in MCF-7 breast cancer cells. Cancer Res 69:3443–3450

    Article  CAS  PubMed  Google Scholar 

  15. Unterholzner S, Willhauck MJ, Cengic N, Schütz M, Göke B, Morris JC, Spitzweg C (2006) Dexamethasone stimulation of retinoic acid-induced sodium iodide symporter expression and cytotoxicity of 131-I in breast cancer cells. J Clin Endocrinol Metab 91:69–78

    Article  CAS  PubMed  Google Scholar 

  16. Kitazono M, Robey R, Zhan Z, Sarlis NJ, Skarulis MC, Aikou T, Bates S, Fojo T (2001) Low concentrations of the histone deacetylase inhibitor, depsipeptide (FR901228), increase expression of the Na(+)/I(+) symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells. J Clin Endocrinol Metab 86:3430–3435

    Article  CAS  PubMed  Google Scholar 

  17. Zarnegar R, Brunaud L, Kanauchi H, Wong M, Fung M, Ginzinger D, Duh QY, Clark OH (2002) Increasing the effectiveness of radioactive iodine therapy in the treatment of thyroid cancer using trichostatin A, a histone deacetylase inhibitor. Surgery 132:984–990

    Article  PubMed  Google Scholar 

  18. Fortunati N, Catalano MG, Arena K, Brignardello E, Piovesan A, Boccuzzi G (2004) Valproic acid induces the expression of the Na+/I+ symporter and iodine uptake in poorly differentiated thyroid cancer cells. J Clin Endocrinol Metab 89:1006–1009

    Article  CAS  PubMed  Google Scholar 

  19. Botrugno OA, Santoro F, Minucci S (2009) Histone deacetylase inhibitors as a new weapon in the arsenal of differentiation therapies of cancer. Cancer Lett 280:134–144

    Article  CAS  PubMed  Google Scholar 

  20. Lee MJ, Kim YS, Kummar S, Giaccone G, Trepel JB (2008) Histone deacetylase inhibitors in cancer therapy. Curr Opin Oncol 20:639–649

    Article  CAS  PubMed  Google Scholar 

  21. Puppin C, D’Aurizio F, D’Elia AV, Cesaratto L, Tell G, Russo D, Filetti S, Ferretti E, Tosi E, Mattei T, Pianta A, Pellizzari L, Damante G (2005) Effects of histone acetylation on sodium iodide symporter promoter and expression of thyroid-specific transcription factors. Endocrinology 146:3967–3974

    Article  CAS  PubMed  Google Scholar 

  22. Atadja P (2009) Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 280:233–241

    Article  CAS  PubMed  Google Scholar 

  23. Behr M, Schmitt TL, Espinoza CR, Loos U (1998) Cloning of a functional promoter of the human sodium/iodide-symporter gene. Biochem J 331:359–363

    CAS  PubMed  Google Scholar 

  24. Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784

    Article  CAS  PubMed  Google Scholar 

  25. Zhou Q, Atadja P, Davidson NE (2007) Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol Ther 6:64–69

    CAS  PubMed  Google Scholar 

  26. Fiskus W, Ren Y, Mohapatra A, Bali P, Mandawat A, Rao R, Herger B, Yang Y, Atadja P, Wu J, Bhalla K (2007) Hydroxamic acid analogue histone deacetylase inhibitors attenuate estrogen receptor-alpha levels and transcriptional activity: a result of hyperacetylation and inhibition of chaperone function of heat shock protein 90. Clin Cancer Res 13:4882–4890

    Article  CAS  PubMed  Google Scholar 

  27. Kim IA, No M, Lee JM, Shin JH, Oh JS, Choi EJ, Kim IH, Atadja P, Bernhard EJ (2009) Epigenetic modulation of radiation response in human cancer cells with activated EGFR or HER-2 signaling: potential role of histone deacetylase 6. Radiother Oncol 92:125–132

    Article  CAS  PubMed  Google Scholar 

  28. Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F, Masson E, Rae P, Laird G, Sharma S, Kantarjian H, Dugan M, Albitar M, Bhalla K (2006) A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 12:4628–4635

    Article  CAS  PubMed  Google Scholar 

  29. Fortunati N, Bertino S, Costantino L, Bosco O, Vercellinatto I, Catalano MG, Boccuzzi G (2008) Valproic acid is a selective antiproliferative agent in estrogen-sensitive breast cancer cells. Cancer Lett 259:156–164

    Article  CAS  PubMed  Google Scholar 

  30. Dohán O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, Ginter CS, Carrasco N (2003) The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Endocr Rev 24:48–77

    Article  PubMed  Google Scholar 

  31. Furuya F, Shimura H, Suzuki H, Taki K, Ohta K, Haraguchi K, Onaya T, Endo T, Kobayashi T (2004) Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin. Endocrinology 145:2865–2875

    Article  CAS  PubMed  Google Scholar 

  32. Beyer SJ, Jimenez RE, Shapiro CL, Cho JY, Jhiang SM (2009) Do cell surface trafficking impairments account for variable cell surface sodium iodide symporter levels in breast cancer? Breast Cancer Res Treat 115:205–212

    Article  CAS  PubMed  Google Scholar 

  33. Kogai T, Ohashi E, Jacobs MS, Sajid-Crockett S, Fisher ML, Kanamoto Y, Brent GA (2008) Retinoic acid stimulation of the sodium/iodide symporter in MCF-7 breast cancer cells is mediated by the insulin growth factor-I/phosphatidylinositol 3-kinase and p38 mitogen activated protein kinase signaling pathways. J Clin Endocrinol Metab 93:1884–1892

    Article  CAS  PubMed  Google Scholar 

  34. Dohán O, De la Vieja A, Carrasco N (2006) Hydrocortisone and purinergic signaling stimulate sodium/iodide symporter (NIS)-mediated iodide transport in breast cancer cells. Mol Endocrinol 20:1121–1137

    Article  PubMed  Google Scholar 

  35. Tanosaki S, Ikezoe T, Heaney A, Said JW, Dan K, Akashi M, Koeffler HP (2003) Effect of ligands of nuclear hormone receptors on sodium/iodide symporter expression and activity in breast cancer cells. Breast Cancer Res Treat 79:335–345

    Article  CAS  PubMed  Google Scholar 

  36. Cho JY, Leveille R, Kao R, Rousset B, Parlow AF, Burak WE Jr, Mazzaferri EL, Jhiang SM (2000) Hormonal regulation of radioiodide uptake activity and NaC/IK symporter expression in mammary glands. J Clin Endocrinol Metab 85:2936–2943

    Article  CAS  PubMed  Google Scholar 

  37. Arturi F, Ferretti E, Presta I, Mattei T, Scipioni A, Scarpelli D, Bruno R, Lacroix L, Tosi E, Gulino A, Russo D, Filetti S (2005) Regulation of iodide uptake and sodium/iodide symporter expression in the MCF-7 human breast cancer cell line. J Clin Endocrinol Metab 90:2321–2326

    Article  CAS  PubMed  Google Scholar 

  38. Knostman KA, McCubrey JA, Morrison CD, Zhang Z, Capen CC, Jhiang SM (2007) PI3K activation is associated with intracellular sodium/iodide symporter protein expression in breast cancer. BMC Cancer 7:137

    Article  PubMed  Google Scholar 

  39. Kogai T, Kanamoto Y, Che LH, Taki K, Moatamed F, Schultz JJ, Brent GA (2004) Systemic retinoic acid treatment induces sodium/iodide symporter expression and radioiodide uptake in mouse breast cancer models. Cancer Res 64:415–422

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Novartis Pharma AG, Basel, Switzerland for providing us LBH589; Giuseppe Damante, Dipartimento di Scienze e Tecnologie Biomediche, Policlinico Universitario di Udine, Udine, Italy, for providing us with the luc-NIS construct; Daniela Taverna and Alessandra Solero, Dipartimento di Scienze Oncologiche, Università di Torino and M. B. C., Torino, Italy, for helping us with luciferase experiments. This study was supported by the Project “Alfieri 2007”, Fondazione CRT, Torino, the Special Project “Oncology”, Compagnia San Paolo, Torino, by MIUR and by Regione Piemonte to Giuseppe Boccuzzi.

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Authors and Affiliations

  1. Oncological Endocrinology, AOU San Giovanni Battista, University of Turin, Turin, Italy

    N. Fortunati, F. Marano, V. Mugoni & G. Boccuzzi

  2. Department of Clinical Pathophysiology, University of Turin, Via Genova 3, 10126, Turin, Italy

    M. G. Catalano, M. Pugliese, O. Bosco & G. Boccuzzi

  3. Novartis Farma S.p.A, Origgio, VA, Italy

    F. Mainini

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  1. N. Fortunati
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Correspondence to G. Boccuzzi.

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Fortunati, N., Catalano, M.G., Marano, F. et al. The pan-DAC inhibitor LBH589 is a multi-functional agent in breast cancer cells: cytotoxic drug and inducer of sodium-iodide symporter (NIS). Breast Cancer Res Treat 124, 667–675 (2010). https://doi.org/10.1007/s10549-010-0789-z

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  • DOI: https://doi.org/10.1007/s10549-010-0789-z

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