Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat)
- 706 Downloads
Aromatase inhibitors (AIs) are important drugs for treating postmenopausal patients with hormone receptor-positive breast cancer. However, acquired resistance to AI therapies is a significant problem. Our study has revealed that the histone deacetylase inhibitor LBH589 treatment abrogated growth of AI-resistant cells in vitro and in vivo, causing cell cycle G2/M arrest and induced apoptosis. LBH589 treatment also reduced the level of NF-κB1 which is overexpressed when AI resistance develops. Analyzing paired tumor specimens from 12 patients, we found that NF-κB1 expression was increased in recurrent AI-resistant tumors as compared to the paired primary tumors before AI treatment. This finding was consistent with up-regulated NF-κB1 expression seen in a collection of well-established AI-resistant cell lines. Furthermore, knockdown of NF-κB1 expression significantly suppressed the proliferation of AI-resistant cells. Treatment of AI-resistant cell lines with LBH589 suppressed NF-κB1 mRNA and protein expression. In addition, LBH589 treatment abrogated growth of AI-resistant tumors in mice, and was associated with significantly decreased levels of NF-κB1 in tumors. In all, our findings strongly support further investigation of LBH589 as a novel therapeutic strategy for patients with AI-resistant breast cancer, in part by suppressing the NF-κB1 pathway.
KeywordsAcquired aromatase inhibitor resistance LBH589 NF-κB1
The research was supported by Susan G. Komen for the Cure (KG080161) and by Grant Number P30 CA033572 from the National Cancer Institute. The authors would like to thank Ms. Sophia Loera, Ms. Lucy Brown, and Dr. Keely Walker for pathologic technical assistance, flow cytometry, and editing this manuscript, and Molly Storer, Meng Wu, and Peter Nguyen for helping with the cell proliferation, animal, and NF-κB1 plasmid experiment, respectively.
Conflict of interest
There are no potential conflicts of interest.
- 3.van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE (2011) Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 377(9762):321–331PubMedCrossRefGoogle Scholar
- 4.Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Lang I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thurlimann B (2011) Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1–98 randomised clinical trial at 8.1 years median follow-up. Lancet Oncol 12(12):1101–1108PubMedCrossRefGoogle Scholar
- 8.Scuto A, Kirschbaum M, Kowolik C, Kretzner L, Juhasz A, Atadja P, Pullarkat V, Bhatia R, Forman S, Yen Y, Jove R (2008) The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph-acute lymphoblastic leukemia cells. Blood 111(10):5093–5100PubMedCrossRefGoogle Scholar
- 17.Munster PN, Thurn KT, Thomas S, Raha P, Lacevic M, Miller A, Melisko M, Ismail-Khan R, Rugo H, Moasser M, Minton SE (2011) A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer 104(12):1828–1835PubMedCrossRefGoogle Scholar
- 18.Yardley D (2011) Entinostat, a novel histone deacetylase inhibitor, added to exemestane improves PFS in advanced breast cancer in a randomized, phase II, double-blind study. Cancer Res 71(24 Suppl.):118sGoogle Scholar
- 19.Drappatz J, Lee EQ, Hammond S, Grimm SA, Norden AD, Beroukhim R, Gerard M, Schiff D, Chi AS, Batchelor TT, Doherty LM, Ciampa AS, Lafrankie DC, Ruland S, Snodgrass SM, Raizer JJ, Wen PY (2012) Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma. J Neurooncol 107(1):133–138PubMedCrossRefGoogle Scholar
- 21.Dickinson M, Ritchie D, DeAngelo DJ, Spencer A, Ottmann OG, Fischer T, Bhalla KN, Liu A, Parker K, Scott JW, Bishton M, Prince HM (2009) Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin lymphoma. Br J Haematol 147(1):97–101PubMedCrossRefGoogle Scholar
- 24.Dai Y, Rahmani M, Dent P, Grant S (2005) Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol Cell Biol 25(13):5429–5444PubMedCrossRefGoogle Scholar
- 29.Prystowsky MB, Adomako A, Smith RV, Kawachi N, McKimpson W, Atadja P, Chen Q, Schlecht NF, Parish JL, Childs G, Belbin TJ (2009) The histone deacetylase inhibitor LBH589 inhibits expression of mitotic genes causing G2/M arrest and cell death in head and neck squamous cell carcinoma cell lines. J Pathol 218(4):467–477PubMedCrossRefGoogle Scholar
- 41.Morris PG, Hudis CA, Giri D, Morrow M, Falcone DJ, Zhou XK, Du B, Brogi E, Crawford CB, Kopelovich L, Subbaramaiah K, Dannenberg AJ (2011) Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res (Phila) 4(7):1021–1029CrossRefGoogle Scholar
- 42.Subbaramaiah K, Howe LR, Bhardwaj P, Du B, Gravaghi C, Yantiss RK, Zhou XK, Blaho VA, Hla T, Yang P, Kopelovich L, Hudis CA, Dannenberg AJ (2011) Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res (Phila) 4(3):329–346CrossRefGoogle Scholar