title: Proteomic identification of predictive biomarkers of resistance to neoadjuvant chemotherapy in luminal breast cancer: a possible role for 14-3-3 theta/tau and tBID?
abstract: BACKGROUND
  Chemotherapy resistance is a major obstacle in effective neoadjuvant treatment for estrogen receptor-positive breast cancer. The ability to predict tumour response would allow chemotherapy administration to be directed towards only those patients who would benefit, thus maximising treatment efficiency. We aimed to identify putative protein biomarkers associated with chemotherapy resistance, using fresh tumour samples with antibody microarray analysis and then to perform pilot clinical validation experiments.
  
  
  METHODS
  Chemotherapy resistant and chemotherapy sensitive tumour samples were collected from breast cancer patients who had received anthracycline based neoadjuvant therapy consisting of epirubicin with cyclophosphamide followed by docetaxel. A total of 5 comparative proteomics experiments were performed using invasive ductal carcinomas which demonstrated estrogen receptor positivity (luminal subtype). Protein expression was compared between chemotherapy resistant and chemotherapy sensitive tumour samples using the Panorama XPRESS Profiler725 antibody microarray containing 725 antibodies from a wide variety of cell signalling and apoptosis pathways. A pilot series of archival samples was used for clinical validation of putative predictive biomarkers.
  
  
  RESULTS
  AbMA analysis revealed 38 differentially expressed proteins which demonstrated at least 1.8 fold difference in expression in chemotherapy resistant tumours and 7 of these proteins (Zyxin, 14-3-3 theta/tau, tBID, Pinin, Bcl-xL, RIP and MyD88) were found in at least 2 experiments. Clinical validation in a pilot series of archival samples revealed 14-3-3 theta/tau and tBID to be significantly associated with chemotherapy resistance.
  
  
  CONCLUSIONS
  For the first time, antibody microarrays have been used to identify proteins associated with chemotherapy resistance using fresh breast cancer tissue. We propose a potential role for 14-3-3 theta/tau and tBID as predictive biomarkers of neoadjuvant chemotherapy resistance in breast cancer. Further validation in a larger sample series is now required.
authors: Cancer Biology Proteomics Group, Postgraduate Medical Institute of the University of Hull, Hull, UK.
authors: Victoria C
authors: VC
authors: Hodgkinson
authors: Dalia
authors: D
authors: ELFadl
authors: Vijay
authors: V
authors: Agarwal
authors: Veerabhadram
authors: V
authors: Garimella
authors: Charlotte
authors: C
authors: Russell
authors: Ervine D
authors: ED
authors: Long
authors: John N
authors: JN
authors: Fox
authors: Penelope L
authors: PL
authors: McManus
authors: Tapan K
authors: TK
authors: Mahapatra
authors: Peter J
authors: PJ
authors: Kneeshaw
authors: Philip J
authors: PJ
authors: Drew
authors: Michael J
authors: MJ
authors: Lind
authors: Lynn
authors: L
authors: Cawkwell
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000008:administration & dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D020360:Neoadjuvant Therapy / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics / Q000379:methods*; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D048948:14-3-3 Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D015415:Biomarkers; D043823:Taxoids; D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide