title: Genomic interaction between ER and HMGB2 identifies DDX18 as a novel driver of endocrine resistance in breast cancer cells.
abstract: 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.
authors.affiliation: 1] Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland [2] Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Redmond
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: Byrne
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: F T
authors.initials: FT
authors.lastname: Bane
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: G D
authors.initials: GD
authors.lastname: Brown
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: P
authors.initials: P
authors.lastname: Tibbitts
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: K
authors.initials: K
authors.lastname: O'Brien
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: A D K
authors.initials: AD
authors.lastname: Hill
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Carroll
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: L S
authors.initials: LS
authors.lastname: Young
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D024261:HMGB2 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D024261:HMGB2 Protein; D011960:Receptors, Estrogen; D013629:Tamoxifen; D056920:Nuclear Receptor Coactivator 1; C529049:DDX18 protein, human; D053487:DEAD-box RNA Helicases