title: Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat).
abstract: 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.
authors.affiliation: Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kubo
authors.forename: Noriko
authors.initials: N
authors.lastname: Kanaya
authors.forename: Karineh
authors.initials: K
authors.lastname: Petrossian
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ye
authors.forename: Charles
authors.initials: C
authors.lastname: Warden
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Reiki
authors.initials: R
authors.lastname: Nishimura
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Osako
authors.forename: Masayuki
authors.initials: M
authors.lastname: Okido
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shimada
authors.forename: Masato
authors.initials: M
authors.lastname: Takahashi
authors.forename: Peiguo
authors.initials: P
authors.lastname: Chu
authors.forename: Yate-Ching
authors.initials: YC
authors.lastname: Yuan
authors.forename: Shiuan
authors.initials: S
authors.lastname: Chen
mesh_terms: D000368:Aged; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D000077289:Letrozole; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D000077767:Panobinostat; D014230:Triazoles / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D052002:NF-kappa B p50 Subunit; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D000077767:Panobinostat; C056516:exemestane