title: S100β as a serum marker in endocrine resistant breast cancer.
abstract: BACKGROUND
  Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer. However, its efficacy is limited by intrinsic and acquired resistance. Here the potential of S100β as a biomarker and inhibition of its signaling network as a therapeutic strategy in endocrine treated patients was investigated.
  
  
  METHODS
  The expression of S100β in tissue and serum was assessed by immunohistochemistry and an enzyme-linked immunosorbent assay, respectively. The S100β signaling network was investigated in cell line models of endocrine resistance by western blot, PCR, immunoprecipitation, and chromatin-immunoprecipitation. Endocrine resistant xenografts and tumor explants from patients with resistant tumors were treated with endocrine therapy in the presence and absence of the p-Src kinase inhibitor, dasatinib.
  
  
  RESULTS
  Tissue and serum levels of S100β were found to predict poor disease-free survival in endocrine-treated patients (n = 509, HR 2.32, 95% CI is 1.58-3.40, p < 0.0001 and n = 187, HR 4.009, 95% CI is 1.66-9.68, p = 0.002, respectively). Moreover, elevated levels of serum S100β detected during routine surveillance over the patient treatment period significantly associated with subsequent clinically confirmed disease recurrence (p = 0.019). In vivo studies demonstrated that endocrine treatment induced transcriptional regulation of S100β which was successfully disrupted with tyrosine kinase inhibition. In endocrine resistant xenografts and tumor explants from patients with endocrine resistant breast cancer, combined endocrine and dasatinib treatment reduced tumor proliferation and down-regulated S100β protein expression in comparison to endocrine treatment alone.
  
  
  CONCLUSIONS
  S100β has potential as a new surveillance tool for patients with ER-positive breast cancer to monitor ongoing response to endocrine therapy. Moreover, endocrine resistant breast cancer patients with elevated S100β may benefit from combined endocrine and tyrosine-kinase inhibitor treatment.
  
  
  BACKGROUND
  ClinicalTrials.gov,  NCT01840293 ). Registered on 23 April 2013. Retrospectively registered.
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Sara
authors.initials: S
authors.lastname: Charmsaz
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Éamon
authors.initials: É
authors.lastname: Hughes
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: Department of Surgery, Beaumont Hospital, Dublin, Ireland.
authors.forename: Paul
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: 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: 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: 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: Jean
authors.initials: J
authors.lastname: McBryan
authors.affiliation: Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
authors.affiliation: Department of Surgery, Lambe Institute for Translational Researcich, National University of Ireland Galway, Galway, Ireland.
authors.forename: Róisín M
authors.initials: RM
authors.lastname: Dwyer
authors.affiliation: Department of Surgery, Lambe Institute for Translational Researcich, National University of Ireland Galway, Galway, Ireland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kerin
authors.affiliation: Department of Surgery, Beaumont Hospital, 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; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood* / Q000378:metabolism; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D064568:S100 Calcium Binding Protein beta Subunit / Q000097:blood* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000627:therapeutic use; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D064568:S100 Calcium Binding Protein beta Subunit; C579160:S100B protein, human; D013629:Tamoxifen
keywords: Biomarker; Breast cancer; Endocrine resistance; Estrogen receptor; S100β