Understanding the Mode of Action of Trastuzumab to Design a Better Therapy for ErbB2-positive Human Breast Cancer

  • Author / Creator
    Elian, Fahed Ah
  • Overexpression of ErbB2 occurs in about 25-30% of breast cancer cases and therefore, represents an attractive therapeutic target for treating breast cancer. There are two models for ErbB2 inhibitors that are currently in clinical use: humanized antibodies directed against ErbB2 and small molecule tyrosine-kinase inhibitors. Patients with ErbB2-positive breast cancer have significantly lower survival rates and a shorter period before relapse than patients without ErbB2 overexpression. Trastuzumab (Herceptin) is a humanized recombinant mAb that binds to the extracellular domain of ErbB2 protein. Although, the exact antitumor mechanisms for trastuzumab are not precisely known, several possibilities have been proposed. Here, we show that trastuzumab is able to block pErbB2 and pEGFR in a ligand-dependent manner. Trastuzumab was able to inhibit both pEGFR and pErbB2 in CHO cell lines that express each receptor alone. Moreover, we show that trastuzumab is able to inhibit the phosphorylation of AKT and Erk that are activated by EGFR and ErbB2 in a ligand-independent manner. Pharmacologically, we found trastuzumab was neither able to significantly inhibit cell proliferation and survival nor enhance the cytotoxic effect of doxorubicin.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Medical Sciences-Medical Genetics
  • Supervisor / co-supervisor and their department(s)
    • Walter, Michael (Medical Genetics)
    • Wang, Zhixiang (Medical Genetics)
  • Examining committee members and their departments
    • Postovit, Lynne-Marie (Oncology)
    • Eisenstat, David (Medical Genetics)
    • Hitt, Mary (Oncology)