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01-01-2013 | Preclinical study

Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat)

Authors: Makoto Kubo, Noriko Kanaya, Karineh Petrossian, Jingjing Ye, Charles Warden, Zheng Liu, Reiki Nishimura, Tomofumi Osako, Masayuki Okido, Kazuo Shimada, Masato Takahashi, Peiguo Chu, Yate-Ching Yuan, Shiuan Chen

Published in: Breast Cancer Research and Treatment | Issue 1/2013

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.

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Title: Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat)
Authors: Makoto Kubo
Noriko Kanaya
Karineh Petrossian
Jingjing Ye
Charles Warden
Zheng Liu
Reiki Nishimura
Tomofumi Osako
Masayuki Okido
Kazuo Shimada
Masato Takahashi
Peiguo Chu
Yate-Ching Yuan
Shiuan Chen
Publication date: 01-01-2013
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-012-2332-x

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