Breast cancer is the second leading cause of cancer death in American women. It is no surprise that women respond to a diagnosis of breast cancer with substantial psychosocial distress. Evidence from psychoneuroimmunology demonstrates that psychosocial distress impairs immune function by reducing natural killer cell activity (NKCA) and the production of interferon (IFN) gamma. Both NKCA and IFN gamma contribute to protection from tumor initiation, primary tumor growth, and tumor metastasis. Of note, epithelial tumors, like those of the breast, are responsive to NK cells and IFN gamma;hence, reductions in these forms of immune defense are relevant to breast cancer. We show that women diagnosed with breast cancer experience psychosocial distress, which is accompanied by elevated levels of cortisol, decreased NKCA, and reduced IFN gamma production. The purpose of this project is to determine whether epigenetic pattern underlies the mechanism for the immune dysregulation that occurs with a diagnosis of breast cancer.
Aim 1 will longitudinally assess women diagnosed with early stage breast cancer and evaluate the trajectory of their psychosocial, cortisol, and immune response with respect to their peripheral blood mononuclear (PBMC) epigenetic pattern.
In Aims 2 and 3, these relationships will be investigated at the cellular and molecular level.
Aim 2 will determine whether PBMC epigenetic pattern is associated with changes in the cellular levels of IFN gamma and/or perforin, two key effector molecules in cancer control.
Aim 3 will determine whether PBMC epigenetic pattern is associated with changes in chromatin accessibility for the promoter regions of IFN gamma and/or perforin. Lastly, Aim 4 will evaluate an explanatory model that posits mediated relationships among the psychobiological variables. Latent growth curve analysis will be used to identify and evaluate the trajectories of the study variables with regard to PBMC epigenetic pattern. This project will provide a mechanistic understanding of immune dysregulation, consequent to psychosocial distress, and has the potential to spur development of new approaches to identify and manage individuals at risk for psychosocial distress mediated immune dysregulation.

Public Health Relevance

Psychosocial distress is acknowledged to affect immune function relevant to cancer control but the molecular mechanism is unknown. One unexplored possibility is that epigenetic modifications result in immune dysfunction and an investigation of an epigenetic basis for immune-dysregulation in cancer patients will provide new insight into the effects of psychosocial-distress and will allow for future development of the means by which to manage this dysregulation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134736-04
Application #
8434283
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Mc Donald, Paige A
Project Start
2010-03-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$510,397
Indirect Cost
$153,137
Name
Loyola University Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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Witek Janusek, Linda; Tell, Dina; Albuquerque, Kevin et al. (2013) Childhood adversity increases vulnerability for behavioral symptoms and immune dysregulation in women with breast cancer. Brain Behav Immun 30 Suppl:S149-62
Bush, Kristin A; Krukowski, Karen; Eddy, Justin L et al. (2012) Glucocorticoid receptor mediated suppression of natural killer cell activity: identification of associated deacetylase and corepressor molecules. Cell Immunol 275:80-9
Mathews, Herbert L; Konley, Teresa; Kosik, Kelly Loster et al. (2011) Epigenetic patterns associated with the immune dysregulation that accompanies psychosocial distress. Brain Behav Immun 25:830-9
Krukowski, Karen; Eddy, Justin; Kosik, Kelly Loster et al. (2011) Glucocorticoid dysregulation of natural killer cell function through epigenetic modification. Brain Behav Immun 25:239-49
Mathews, Herbert L; Janusek, Linda Witek (2011) Epigenetics and psychoneuroimmunology: mechanisms and models. Brain Behav Immun 25:25-39