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Understanding Tamoxifen Resistance in Breast cancer

  • Author / Creator
    Bekele, Raie Taye
  • Tamoxifen is the accepted therapy for patients with estrogen receptor α (ERα)−positive breast cancer. However, clinical resistance to tamoxifen, as demonstrated by recurrence or progression on therapy, is frequent and precedes death from metastases. To improve breast cancer treatment it is vital to understand the mechanisms that result in tamoxifen resistance. The study presented in this thesis shows that concentration of tamoxifen and its metabolites, which accumulate in tumors of patients, killed breast cancer cells by inducing oxidative stress. Breast cancer cells responded to tamoxifen-induced oxidation by increasing Nrf2 expression and subsequent activation of the anti-oxidant response element (ARE). This increased the transcription of anti-oxidant genes and multidrug resistance transporters. As a result, breast cancer cells are able to destroy or export toxic oxidation products leading to increased survival from tamoxifen-induced oxidative damage. These responses in cancer cells also occur in breast tumors of tamoxifen-treated mice. Additionally, high levels of expression of Nrf2 and its downstream targets in breast tumors of patients at the time of diagnosis were prognostic of poor survival after tamoxifen therapy. The oxidative stress induced by tamoxifen also activated phospholipase D (PLD) and led to the up regulation of the RALBP1 (Ral-binding protein 1). Tamoxifen resistant cells also had a significant increase in both basal and stimulated PLD activity along with increased PLD1 and RALBP1 levels. The activity of PLD provides survival signals to cancer cells, whereas RALBP1 exports chemotherapeutic drugs. Thus both RALBP1 and PLD in concert can lead to development of an aggressive and metastatic breast cancers and also contribute to chemo-resistance. In our study, cancerous breast tissues from patients have a significantly higher expression of RALBP1 compared to normal breast tissue. Furthermore, cytotoxic chemotherapy combination offered no significant advantage in patient cohorts with high RALBP1 expression as compared to those patients receiving mono or non-cytotoxic chemotherapies. Moreover, patients with high expression of PLD1 also had poor prognostic outcomes to different treatments. Thus, overcoming adaptive responses to tamoxifen-induced oxidative stress could improve the survival of breast cancer patients.

  • Subjects / Keywords
  • Graduation date
    2016-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3BG2HJ5B
  • 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
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Biochemistry
  • Supervisor / co-supervisor and their department(s)
    • Brindley, David N. (University of Alberta, Biochemistry)
  • Examining committee members and their departments
    • Fliegel, Larry (University of Alberta, Biochemistry)
    • Wang, Zhixiang (University of Alberta, Medical Genetics)
    • Morris, Andrew J. (Cardiovascular Medicine and Pharmacology, University of Kentucky)
    • Fahlman, Richard (University of Alberta, Biochemistry)
    • Goping, Ing Swie (University of Alberta, Biochemistry)