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Permanent link (DOI): https://doi.org/10.7939/R33H67

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Mechanisms of MUC1/ICAM-1 signalling in breast cancer metastasis Open Access

Descriptions

Other title
Subject/Keyword
Breast Cancer
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Bernier, Ashlyn
Supervisor and department
Hugh, Judith (Laboratory Medicine and Pathology)
Examining committee member and department
Le, Chris (Laboratory Medicine and Pathology)
Goping, Ing Swie (Biochemistry)
Mukherjee, Pinku (Biochemistry)
Shaw, Andrew (Oncology)
Department
Medical Sciences - Laboratory Medicine and Pathology
Specialization

Date accepted
2011-09-27T22:06:41Z
Graduation date
2011-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Breast cancer is the second leading cause of cancer death in Canadian women. In these patients, mortality is due to metastasis of cancer cells from the breast to distant organs, resulting in impairment of function. To metastasize, cells must move through the stroma of the breast, enter the circulation, survive transit, exit the circulation, and form a secondary tumor. A critical component of this metastatic cascade is cancer cell motility. It is not fully understood how breast cancer cells gain the ability to move or what signaling pathways mediate these events, and identification of critical components of these pathways would represent potential targets for anti-metastatic therapies. The MUC1 glycoprotein is expressed on the apical membrane of normal breast epithelia. In many human breast carcinomas, MUC1 is overexpressed and loses apical polarization, events that correlate with increased metastasis. The contribution of MUC1 overexpression to increased metastasis is not completely understood, with the majority of studies attributing an anti-adhesive role to MUC1. Several critical steps of the metastatic cascade require cell adhesion, and it has been reported that MUC1 is a ligand for ICAM-1, which is expressed throughout the migratory tract of a metastasizing breast cancer cell. It was subsequently reported that MUC1/ICAM-1 binding initiates calcium oscillations, cytoskeletal reorganization, and cell migration, suggesting that binding could be important in metastasis. Here, we investigate the mechanism of MUC1/ICAM-1 binding induced signaling. We show that Src kinase is a critical component of the MUC1/ICAM-1 signalling axis, and that MUC1 forms constitutive dimers which are required for Src recruitment and ICAM-1 binding induced signaling. We show that MUC1 dimers are not covalently linked and do not require cytoplasmic domain cysteine residues, contrary to other reports. We show that MUC1 extracellular domain shedding is not required for dimerization, Src recruitment, or ICAM-1 binding induced calcium oscillations, although it is required for migration. Lastly, we show that autoproteolytic cleavage of MUC1 is not required for normal function. These results reveal information on the mechanism of MUC1/ICAM-1 signalling, which can be used to identify novel targets and combinational strategies for anti-metastatic therapy in breast cancer.
Language
English
DOI
doi:10.7939/R33H67
Rights
License granted by Ashlyn Bernier (ashlyn@ualberta.ca) on 2011-09-23T22:06:26Z (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: Microsoft Word - Sept 11 thesis body.docx
File author: Ashlyn Bernier
Page count: 246
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