title: Adaptation to AI Therapy in Breast Cancer Can Induce Dynamic Alterations in ER Activity Resulting in Estrogen-Independent Metastatic Tumors.
abstract: Acquired resistance to aromatase inhibitor (AI) therapy is a major clinical problem in the treatment of breast cancer. The detailed mechanisms of how tumor cells develop this resistance remain unclear. Here, the adapted function of estrogen receptor (ER) to an estrogen-depleted environment following AI treatment is reported.
  
  
  
  Global ER chromatin immuno-precipitation (ChIP)-seq analysis of AI-resistant cells identified steroid-independent ER target genes. Matched patient tumor samples, collected before and after AI treatment, were used to assess ER activity.
  
  
  
  Maintained ER activity was observed in patient tumors following neoadjuvant AI therapy. Genome-wide ER-DNA-binding analysis in AI-resistant cell lines identified a subset of classic ligand-dependent ER target genes that develop steroid independence. The Kaplan-Meier analysis revealed a significant association between tumors, which fail to decrease this steroid-independent ER target gene set in response to neoadjuvant AI therapy, and poor disease-free survival and overall survival (n = 72 matched patient tumor samples, P = 0.00339 and 0.00155, respectively). The adaptive ER response to AI treatment was highlighted by the ER/AIB1 target gene, early growth response 3 (EGR3). Elevated levels of EGR3 were detected in endocrine-resistant local disease recurrent patient tumors in comparison with matched primary tissue. However, evidence from distant metastatic tumors demonstrates that the ER signaling network may undergo further adaptations with disease progression as estrogen-independent ER target gene expression is routinely lost in established metastatic tumors.
  
  
  
  Overall, these data provide evidence of a dynamic ER response to endocrine treatment that may provide vital clues for overcoming the clinical issue of therapy resistance. Clin Cancer Res; 22(11); 2765-77. ©2016 AACR.
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Damir
authors.initials: D
authors.lastname: Varešlija
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Jean
authors.initials: J
authors.lastname: McBryan
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Ailís
authors.initials: A
authors.lastname: Fagan
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Aisling M
authors.initials: AM
authors.lastname: Redmond
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hao
authors.affiliation: University of Edinburgh Cancer Research Centre, Carrington Crescent, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sims
authors.affiliation: University of Edinburgh Cancer Research Centre, Carrington Crescent, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Arran
authors.initials: A
authors.lastname: Turnbull
authors.affiliation: University of Edinburgh Cancer Research Centre, Carrington Crescent, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: J M
authors.initials: JM
authors.lastname: Dixon
authors.affiliation: School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Peadar
authors.initials: P
authors.lastname: Ó Gaora
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Lance
authors.initials: L
authors.lastname: Hudson
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Purcell
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Arnold D K
authors.initials: AD
authors.lastname: Hill
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland. lyoung@rcsi.ie.
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Young
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000517:prevention & control / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D051776:Early Growth Response Protein 3 / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000517:prevention & control / Q000556:secondary; D061986:MCF-7 Cells; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D002352:Carrier Proteins; C079945:EGR3 protein, human; C000609551:MREG protein, human; D011960:Receptors, Estrogen; D051776:Early Growth Response Protein 3; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3