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Permanent link (DOI): https://doi.org/10.7939/R3D71C

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Exploring Notch signaling pathways for breast cancer treatment Open Access

Descriptions

Other title
Subject/Keyword
Breast cancer
Notch signaling
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Han, Jianxun
Supervisor and department
Turner, Joan (Oncology)
Hendzel, Michael (Oncology)
Examining committee member and department
Chan, Gordon (Oncology)
Karsan, Aly (Pathology and Laboratory Medicine, University of British Columbia)
Hugh, Judith (Laboratory Medicine & Pathology)
Murray, David (Oncology)
Hendzel, Michael (Oncology)
Turner, Joan (Oncology)
Department
Department of Oncology
Specialization

Date accepted
2010-08-20T16:32:23Z
Graduation date
2010-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Breast cancer is the most common cancer and the leading cause of cancer-related death among Canadian women. Despite improvements in treatment and early detection, there is still a need to develop novel therapies for breast cancer management. Aberrant Notch signaling is tumorigenic and is associated with poor clinical outcomes in breast cancer, as well as in several other types of cancer. Activation of Notch signaling requires γ-secretase-mediated Notch receptor cleavage. Thus, strategies to inhibit Notch signaling, including γ-secretase inhibition, are being evaluated for potential anti-tumor effects. The strongest justification for targeting Notch in breast cancer, and more specifically for using γ-secretase inhibitors, came from two studies that reported that the γ-secretase inhibitor (GSI) Z-LLNle-CHO inhibited the growth of breast cancer cells both in vitro and in vivo without causing significant side effects. In Chapter 2, we compared the enzymatic activities and cytotoxicity of Z-LLNle-CHO to those of two other specific GSIs and three proteasome inhibitors and demonstrated that the cytotoxicity of Z-LLNle-CHO in breast cancer cells is mediated by proteasome inhibition, not by γ-secretase inhibition. In Chapter 3, we characterized the protein complexes formed in breast cancer cells by the intracellular domains (NICD) of the four Notch paralogs. We found that the assembly of NICD protein complexes is dose-dependent and availability of MAML proteins becomes the limiting factor for continuous formation of NICD/RBPjκ/MAML transactivation complex. This suggests that the formation of some non-canonical NICD complex might occur preferentially at high levels of NICD, conditions under which aberrant Notch signaling induces tumorigenesis in breast cancer. Consequently, these non-canonical interactions might be good targets to specifically block oncogenic, but not physiological, Notch signaling. In addition, we found that the relative affinities of individual NICD paralogs to several known NICD-interacting proteins were different. This may account for the paralog-specific activities of Notch that have been previously reported. Together, these results may be of value for the development of new reagents to block Notch signaling for therapeutic benefit in breast cancer treatment.
Language
English
DOI
doi:10.7939/R3D71C
Rights
License granted by Jianxun Han (jianxun@ualberta.ca) on 2010-08-16T20:39:50Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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File title: Breast cancer is the most common malignant tumour among Canadian women, and despite the improvements in treatment and early detection by annual mammography screening in the past two decades, it still remains to be the leading cause of cancer-relat...
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