ABSTRACT
Breast cancer is a complex disease, whose etiology is not well understood. A
number of factors have been found to contribute to its development. Psychological stress
has been recognized as such a factor in epidemiological studies, but few molecular
mechanisms have been proposed to explain its association to breast cancer risk. This
work addresses the lack of knowledge in the area of stress and breast cancer with the use
of molecular and epidemiological techniques. Molecular experiments allowed the
identification of a link between stress signaling and intracellular signaling pathways
known to be affected in breast cancer development. Namely, the stress hormone
hydrocortisone (cortisol) was found to down-regulate the Breast Cancer Susceptibility
Gene 1 (BRCA1). Further study allowed identification of some of the mechanisms
involved. Binding of the transcription factors GABPa/b and USF2 at specific sites of the
BRCA1 promoter (the RIBS and UP sites) was shown to be negatively affected by
hydrocortisone. In addition, a novel hormone-independent function of the receptor for
hydrocortisone, the glucocorticoid receptor, was identified in the context of BRCA1
regulation. GR was determined to act as a positive regulator of BRCA1 in the absence of
hydrocortisone through the RIBS and UP sites. Taken altogether these results represent a
novel molecular mechanism linking stress signaling to breast cancer development.
The second objective of this work was to design an epidemiological study which
would determine whether stress-susceptible individuals are at higher risk of developing
breast cancer. This study would be the first of its kind in the case of breast cancer and
would allow the development of a genetic method of measuring stress exposure which
can be used in future studies. The study was designed to look at glucocorticoid receptor
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polymorphisms known to produce phenotypic differences in GR activity in a population
of women with incident breast cancer and population-based controls. In conclusion, the
present work suggests an integrative model of the effect of stress on breast cancer
development which incorporates genetic predisposition to the effects of stress and
downstream changes in the expression and activity of the Breast Cancer Susceptibility
Gene 1. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2008-01-02 23:42:20.89 / Canadian Breast Cancer Foundation-Ontario Chapter
Canadian Institute of Health Research
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OKQ.1974/986 |
| Date | 15 January 2008 |
| Creators | Antonova, Lilia |
| Contributors | Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | 3729859 bytes, application/pdf |
| Rights | This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner. |
| Relation | Canadian theses |
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