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Permanent link (DOI): https://doi.org/10.7939/R3BG2HJ5B

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Understanding Tamoxifen Resistance in Breast cancer Open Access

Descriptions

Other title
Subject/Keyword
Phospholipase D1/2
Nrf2
Lysophosphatidate
Tamoxifen
Oxidative stress
Breast cancer
Chemo-resistance
Chemotherapy
Anthracyclines
RALBP1
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Bekele, Raie Taye
Supervisor and department
Brindley, David N. (University of Alberta, Biochemistry)
Examining committee member and department
Wang, Zhixiang (University of Alberta, Medical Genetics)
Goping, Ing Swie (University of Alberta, Biochemistry)
Fahlman, Richard (University of Alberta, Biochemistry)
Fliegel, Larry (University of Alberta, Biochemistry)
Morris, Andrew J. (Cardiovascular Medicine and Pharmacology, University of Kentucky)
Department
Department of Biochemistry
Specialization

Date accepted
2016-03-16T15:51:44Z
Graduation date
2016-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R3BG2HJ5B
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. 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.
Citation for previous publication
Bekele RT, Venkatraman G, Liu R, Tang X, Mi S, Benesch MG, Mackey JR, Godbout R, Curtis JM, McMullen TP, Brindley DN. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance. Nature Sci. Rep. 6, 21164; doi: 10.1038/srep21164 (2016).Benesch MG, Tang X, Venkatraman G, Bekele RT, Brindley DN. Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo. J Biomed Res. 2015 Aug 28;30. doi: 10.7555/JBR.29.20150058.Bekele RT, Brindley DN: Role of autotaxin and lysophosphatidate in cancer progression and resistance to chemotherapy and radiotherapy. Clinical Lipidology 7(3), 313-328 (2012). doi:10.2217/clp.12.30Samadi N, Bekele RT, Goping IS, Schang LM, Brindley DN: Lysophosphatidate induces chemo-resistance by releasing breast cancer cells from taxol-induced mitotic arrest. PLoS One 6(5), e20608 (2011). doi: 10.1371/journal.pone.0020608.Samadi N, Bekele RT, Capatos D, Venkatraman G, Sariahmetoglu M, Brindley DN: Regulation of lysophosphatidate signaling by autotaxin and lipid phosphate phosphatases with respect to tumor progression, angiogenesis, metastasis and chemo-resistance. Biochimie 93(1), 61-70 (2011). doi: 10.1016/j.biochi.2010.08.002.

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