BMB Reports 2018; 51(9): 450-455  https://doi.org/10.5483/BMBRep.2018.51.9.020
Up-regulation of HOXB cluster genes are epigenetically regulated in tamoxifen-resistant MCF7 breast cancer cells
Seoyeon Yang1,2,#, Ji-Yeon Lee1,#, Ho Hur3, Ji Hoon Oh1,2 & Myoung Hee Kim1,2,*
1Department of Anatomy, Embryology Laboratory, and 2Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, 3Department of Surgery, National Health Insurance Service Ilsan Hospital, Goyang 10444, Korea
Correspondence to: Tel: +82-2-2228-1647; Fax: +82-2-365-0700; E-mail: mhkim1@yuhs.ac
#These authors contributed equally to this work.
Received: January 30, 2018; Revised: March 7, 2018; Accepted: April 26, 2018; Published online: September 30, 2018.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Tamoxifen (TAM) is commonly used to treat estrogen receptor (ER)-positive breast cancer. Despite the remarkable benefits, resistance to TAM presents a serious therapeutic challenge. Since several HOX transcription factors have been proposed as strong candidates in the development of resistance to TAM therapy in breast cancer, we generated an in vitro model of acquired TAM resistance using ER-positive MCF7 breast cancer cells (MCF7-TAMR), and analyzed the expression pattern and epigenetic states of HOX genes. HOXB cluster genes were uniquely up-regulated in MCF7-TAMR cells. Survival analysis of in slico data showed the correlation of high expression of HOXB genes with poor response to TAM in ER-positive breast cancer patients treated with TAM. Gain- and loss-of-function experiments showed that the overexpression of multi HOXB genes in MCF7 renders cancer cells more resistant to TAM, whereas the knockdown restores TAM sensitivity. Furthermore, activation of HOXB genes in MCF7-TAMR was associated with histone modifications, particularly the gain of H3K9ac. These findings imply that the activation of HOXB genes mediate the development of TAM resistance, and represent a target for development of new strategies to prevent or reverse TAM resistance.
Keywords: Breast cancer, Histone modification, HOX genes, Tamoxifen resistance


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Funding Information
  • Ministry of Science, ICT and Future Planning(MSIP)
      10.13039/501100003621
     
  • National Research Foundation of Korea(NRF)
      10.13039/501100003725
      NRF-2014R1A1A2056986, NRF-2016R1D1A1B03930822, NRF-2016R1A2B2011821

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