title: Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance.
abstract: BACKGROUND
  In breast cancer, overexpression of the transmembrane tyrosine kinase ERBB2 is an adverse prognostic marker, and occurs in almost 30% of the patients. For therapeutic intervention, ERBB2 is targeted by monoclonal antibody trastuzumab in adjuvant settings; however, de novo resistance to this antibody is still a serious issue, requiring the identification of additional targets to overcome resistance. In this study, we have combined computational simulations, experimental testing of simulation results, and finally reverse engineering of a protein interaction network to define potential therapeutic strategies for de novo trastuzumab resistant breast cancer.
  
  
  RESULTS
  First, we employed Boolean logic to model regulatory interactions and simulated single and multiple protein loss-of-functions. Then, our simulation results were tested experimentally by producing single and double knockdowns of the network components and measuring their effects on G1/S transition during cell cycle progression. Combinatorial targeting of ERBB2 and EGFR did not affect the response to trastuzumab in de novo resistant cells, which might be due to decoupling of receptor activation and cell cycle progression. Furthermore, examination of c-MYC in resistant as well as in sensitive cell lines, using a specific chemical inhibitor of c-MYC (alone or in combination with trastuzumab), demonstrated that both trastuzumab sensitive and resistant cells responded to c-MYC perturbation.
  
  
  CONCLUSIONS
  In this study, we connected ERBB signaling with G1/S transition of the cell cycle via two major cell signaling pathways and two key transcription factors, to model an interaction network that allows for the identification of novel targets in the treatment of trastuzumab resistant breast cancer. Applying this new strategy, we found that, in contrast to trastuzumab sensitive breast cancer cells, combinatorial targeting of ERBB receptors or of key signaling intermediates does not have potential for treatment of de novo trastuzumab resistant cells. Instead, c-MYC was identified as a novel potential target protein in breast cancer cells.
authors.affiliation: German Cancer Research Center, Heidelberg, Germany. oe.sahin@dkfz-heidelberg.de
authors.forename: Ozgür
authors.initials: O
authors.lastname: Sahin
authors.forename: Holger
authors.initials: H
authors.lastname: Fröhlich
authors.forename: Christian
authors.initials: C
authors.lastname: Löbke
authors.forename: Ulrike
authors.initials: U
authors.lastname: Korf
authors.forename: Sara
authors.initials: S
authors.lastname: Burmester
authors.forename: Meher
authors.initials: M
authors.lastname: Majety
authors.forename: Jens
authors.initials: J
authors.lastname: Mattern
authors.forename: Ingo
authors.initials: I
authors.lastname: Schupp
authors.forename: Claudine
authors.initials: C
authors.lastname: Chaouiya
authors.forename: Denis
authors.initials: D
authors.lastname: Thieffry
authors.forename: Annemarie
authors.initials: A
authors.lastname: Poustka
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.forename: Tim
authors.initials: T
authors.lastname: Beissbarth
authors.forename: Dorit
authors.initials: D
authors.lastname: Arlt
mesh_terms: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D015202:Protein Engineering / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004268:DNA-Binding Proteins; C116115:MYCBP protein, human; D014157:Transcription Factors; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068878:Trastuzumab