Genomic interaction between ER and HMGB2 identifies DDX18 as a novel driver of endocrine resistance in breast cancer cells

Oncogene. 2015 Jul;34(29):3871-80. doi: 10.1038/onc.2014.323. Epub 2014 Oct 6.


Breast cancer resistance to endocrine therapies such as tamoxifen and aromatase inhibitors is a significant clinical problem. Steroid receptor coactivator-1 (SRC-1), a coregulatory protein of the oestrogen receptor (ER), has previously been shown to have a significant role in the progression of breast cancer. The chromatin protein high mobility group box 2 (HMGB2) was identified as an SRC-1 interacting protein in the endocrine-resistant setting. We investigated the expression of HMGB2 in a cohort of 1068 breast cancer patients and found an association with increased disease-free survival time in patients treated with endocrine therapy. However, it was also verified that HMGB2 expression could be switched on in endocrine-resistant tumours from breast cancer patients. To explore the function of this poorly characterized protein, we performed HMGB2 ChIPseq and found distinct binding patterns between the two contexts. In the resistant setting, the HMGB2, SRC-1 and ER complex are enriched at promoter regions of target genes, with bioinformatic analysis indicating a switch in binding partners between the sensitive and resistant phenotypes. Integration of binding and gene expression data reveals a concise set of target genes of this complex including the RNA helicase DDX18. Modulation of DDX18 directly affects growth of tamoxifen-resistant cells, suggesting that it may be a critical downstream effector of the HMGB2:ER complex. This study defines HMGB2 interactions with the ER complex at specific target genes in the tamoxifen-resistant setting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • HMGB2 Protein / genetics
  • HMGB2 Protein / metabolism*
  • Humans
  • Kaplan-Meier Estimate
  • MCF-7 Cells
  • Mice, Inbred BALB C
  • Mice, SCID
  • Nuclear Receptor Coactivator 1 / genetics
  • Nuclear Receptor Coactivator 1 / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA Interference
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tamoxifen / pharmacology
  • Tamoxifen / therapeutic use
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Hormonal
  • HMGB2 Protein
  • Receptors, Estrogen
  • Tamoxifen
  • Nuclear Receptor Coactivator 1
  • DDX18 protein, human
  • DEAD-box RNA Helicases