Molecular Stress Signaling in Breast Epithelial Cells

• Main Author: Antonova, Lilia
• Other Authors: Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))
• Format: Others
• Language: en; en
• Published: 2007
• Subjects: molecular; breast cancer; BRCA1; stress; hydrocortisone
• Online Access: http://hdl.handle.net/1974/986

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 iii 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