title: Receptor Tyrosine Kinase Expression Predicts Response to Sunitinib in Breast Cancer.
abstract: BACKGROUND
  Preliminary data indicate that tyrosine kinase inhibitors (TKIs) function through rearranged during transfection (RET) in breast cancer. However, TKIs are not specific and can block several receptor tyrosine kinases (RTKs). This study used cell lines and primary breast cancer specimens to determine factors associated with TKI response.
  
  
  METHODS
  Proliferation was assessed after short interfering RNA knockdown with or without sunitinib in breast cancer cell lines by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Breast cancer tissue and matched normal breast was obtained from 30 women with invasive breast carcinoma. Gene expression was assessed by reverse transcriptase-polymerase chain reaction. Fresh tissue was treated in vitro with sunitinib or control media for 30 min, and response was assessed by phosphorylation-specific western blot.
  
  
  RESULTS
  The RTKs including epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR1-3), platelet-derived growth factor receptor (PDGFRa/b), and Kit were overexpressed in triple-negative breast tumors relative to HER2- and estrogen receptor-alpha (ERα)-positive tumors and normal breast tissue. Knockdown of EGFR reduced in vitro proliferation in MCF-7 and MDA-MB-231 but not in SKBR-3 or ZR-75-1 breast cancer cells. With the exception of RET, response to sunitinib was independent of RTK expression in all four cell lines. Both ERα-positive and low-EGFR-expressing tumors had an increased in vitro sunitinib response, as determined by alteration of Erk activation. Expression of other RTKs and additional clinical factors were not associated with response.
  
  
  CONCLUSIONS
  Triple-negative breast cancers overexpress RTKs but have decreased in vitro response to the TKI sunitinib. In addition to RET, TKIs that block EGFR may increase the therapeutic efficacy of TKIs in breast cancer.
authors.affiliation: Department of Surgery, University of Iowa, Iowa City, IA, USA.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Spanheimer
authors.affiliation: Department of Surgery, University of Iowa, Iowa City, IA, USA.
authors.forename: Allison W
authors.initials: AW
authors.lastname: Lorenzen
authors.affiliation: Department of Surgery, University of Iowa, Iowa City, IA, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: De Andrade
authors.affiliation: Department of Surgery, University of Iowa, Iowa City, IA, USA.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Kulak
authors.affiliation: Department of Surgery, University of Iowa, Iowa City, IA, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Carr
authors.affiliation: Department of Surgery, University of Iowa, Iowa City, IA, USA.
authors.forename: George W
authors.initials: GW
authors.lastname: Woodfield
authors.affiliation: Department of Surgery, University of Iowa, Iowa City, IA, USA.
authors.forename: Sonia L
authors.initials: SL
authors.lastname: Sugg
authors.affiliation: Department of Surgery, University of Iowa, Iowa City, IA, USA. ronald-Weigel@uiowa.edu.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Weigel
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008875:Middle Aged; D009367:Neoplasm Staging; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D014407:Tumor Cells, Cultured
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077210:Sunitinib