title: Transcriptomic Profiling of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic Expression Changes Following Endocrine Therapy.
abstract: OBJECTIVE
  Disease recurrence is a common problem in breast cancer and yet the mechanisms enabling tumor cells to evade therapy and colonize distant organs remain unclear. We sought to characterize global expression changes occurring with metastatic disease progression in the endocrine-resistant setting.
  
  
  METHODS
  Here, for the first time, RNAsequencing has been performed on matched primary, nodal, and liver metastatic tumors from tamoxifen-treated patients following disease progression. Expression of genes commonly elevated in the metastases of sequenced patients was subsequently examined in an extended matched patient cohort with metastatic disease from multiple sites. The impact of tamoxifen treatment on endocrine-resistant tumors in vivo was investigated in a xenograft model.
  
  
  RESULTS
  The extent of patient heterogeneity at the gene level was striking. Less than 3% of the genes differentially expressed between sequential tumors were common to all patients. Larger divergence was observed between primary and liver tumors than between primary and nodal tumors, reflecting both the latency to disease progression and the genetic impact of intervening therapy. Furthermore, an endocrine-resistant in vivo mouse model demonstrated that tamoxifen treatment has the potential to drive disease progression and establish distant metastatic disease. Common functional pathways altered during metastatic, endocrine-resistant progression included extracellular matrix receptor interactions and focal adhesions.
  
  
  CONCLUSIONS
  This novel global analysis highlights the influence of primary tumor biology in determining the transcriptomic profile of metastatic tumors, as well as the need for adaptations in cell-cell communications to facilitate successful tumor cell colonization of distant host organs.
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, 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, Ireland.
authors.forename: Ailís
authors.initials: A
authors.lastname: Fagan
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Damian
authors.initials: D
authors.lastname: McCartan
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Fiona T
authors.initials: FT
authors.lastname: Bane
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, 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, Ireland.
authors.forename: Sinéad
authors.initials: S
authors.lastname: Cocchiglia
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Christopher
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: Jarlath
authors.initials: J
authors.lastname: Bolger
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Marie
authors.initials: M
authors.lastname: McIlroy
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, 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, Ireland.
authors.forename: Paul
authors.initials: P
authors.lastname: Tibbitts
authors.affiliation: UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Peadar Ó
authors.initials: PÓ
authors.lastname: Gaora
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Arnold D
authors.initials: AD
authors.lastname: Hill
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland. lyoung@rcsi.ie.
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Young
mesh_terms: D000328:Adult; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D003131:Combined Modality Therapy; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D059467:Transcriptome; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers