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Breast cancer, Notch signaling

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 and 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 goodtargets 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.





Author: Han, Jianxun

Source: https://era.library.ualberta.ca/


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University of Alberta Exploring Notch signaling pathways for breast cancer treatment by Jianxun Han A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Experimental Oncology Department of Oncology ©Jianxun Han Fall 2010 Edmonton, Alberta 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 these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the authors prior written permission. Examining Committee Joan Turner, Oncology Michael Hendzel, Oncology David Murrary, Oncology Gordon Chan, Oncology Judith Hugh, Laboratory Medicine & Pathology Aly Karsan, Pathology and Laboratory Medicine, University of British Columbia To my family Abstract Breast cancer is the most common cancer and the leading cause of cancerrelated 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 signalling is tumorigenic and is associated with poor clinical outcomes in breast cancer, as well as in several other types of cancer.
Activation of Notch signalling requires γ-secretase-mediated Notch receptor cleavage.
Thus, strategies to inhibit Notch signalling, including γsecretase inhibition, are being evaluated for potential anti-tumor effects.
The strongest justification for targeting Notch in breast cancer, and more specifically for ...





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