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

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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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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA

    Makoto Kubo, Noriko Kanaya, Karineh Petrossian, Jingjing Ye & Shiuan Chen

  2. Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA

    Charles Warden, Zheng Liu & Yate-Ching Yuan

  3. Department of Breast & Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Japan

    Reiki Nishimura & Tomofumi Osako

  4. Department of Breast Surgery, Hamanomachi Hospital, Fukuoka, Japan

    Masayuki Okido

  5. Shimada Breast & Surgery Clinic, Kitakyushu, Japan

    Kazuo Shimada

  6. Department of Breast Surgery, Hokkaido Cancer Center, National Hospital Organization, Sapporo, Japan

    Masato Takahashi

  7. Department of Pathology, Beckman Research Institute of the City of Hope, Duarte, CA, United States of America

    Peiguo Chu

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  1. Makoto Kubo
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  2. Noriko Kanaya
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  3. Karineh Petrossian
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  13. Yate-Ching Yuan
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  14. Shiuan Chen
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Corresponding author

Correspondence to Shiuan Chen.

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Makoto Kubo and Noriko Kanaya contributed equally to this study.

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Kubo, M., Kanaya, N., Petrossian, K. et al. Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat). Breast Cancer Res Treat 137, 93–107 (2013). https://doi.org/10.1007/s10549-012-2332-x

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  • DOI: https://doi.org/10.1007/s10549-012-2332-x

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