Steven W. Cole, PhD

2012-2013 BCRF Project:
(made possible by generous support from Clinique)

Co-Investigator: Julienne E. Bower, PhD, David Geffen School of Medicine, University of California, Los Angeles, CA

The role of stress in breast cancer initiation and progression has long been of interest to researchers, clinicians, and patients, although empirical research on this topic has yielded mixed and inconclusive results. A major barrier to investigating linkages between stress and breast cancer has been the lack of knowledge about biological pathways that may mediate these effects. Over the past decade, inflammation has emerged as a plausible biological pathway linking stress and breast cancer outcomes. The role of inflammation in tumor growth and progression is now well established, with tumor-associated inflammatory cells including macrophages facilitating many of the hallmark characteristics of cancer (e.g. proliferation, angiogenesis, resistance to cell death, invasion, metastasis). There is also compelling evidence linking inflammation and psychological stress. In the laboratory, chronic stress is seen to increase macrophage trafficking and activation, leading to increased production of pro-inflammatory cytokines. In clinical studies, exposure to acute (e.g., public speaking) and chronic stressors (e.g. caregiving, chronic interpersonal problems) has been reliably linked with increases in pro-inflammatory cytokine activity.

Earlier preclinical data from Drs. Bower and Cole offer initial support for the hypothesis that stress may induce breast cancer progression via effects on inflammatory processes, specifically effects on tumor-associated macrophages. Although research on stress and inflammation in clinical cancer populations is extremely limited, preliminary evidence suggests a link between psychological stress and tumor-associated markers of inflammation in women with ovarian cancer. However, the relationship between stress and inflammatory processes, particularly in the tumor microenvironment, has not been examined in breast cancer patients.

Drs. Bower and Cole are currently enrolling women with early stage breast cancer to evaluate the association between chronic psychological stress and tumor-associated immune responses. They are conducting interviews with women to assess stressful events that may have occurred throughout their lifetimes and particularly in the years prior to cancer diagnosis. In addition, they are collecting tumor samples from these women to determine whether there are links between stress exposure and immune cells in the tumor microenvironment that may predispose to negative clinical outcomes.

This work aims to advance our understanding of links between psychological stress and breast cancer and identify possible targets for intervention.

Mid-year Progress: This project continues to investigate links between psychological stress and characteristics of immune cells known to be important for the growth and spread of breast tumors. Macrophages are a type of immune cell that plays a key role in tumor initiation, progression, and metastasis. Macrophages appear to be sensitive to psychological stress in healthy individuals, but these links have not been evaluated in breast cancer patients. In the current study, Drs. Bower and Cole are examining the association between lifetime stress exposure and tumor-promoting macrophages in newly diagnosed breast cancer patients and in healthy breast cancer survivors. In addition, they are investigating the neural underpinnings of chronic stress exposure to determine how stress may become embedded in the brain to influence cancer progression.

Drs. Bower and Cole are currently in the process of analyzing data to determine whether women with high lifetime stress exposure show elevated inflammatory/metastatic gene expression. As their current year's BCRF project is designed to expand upon this work to provide a more integrated understanding of the mechanisms through which stress may impact inflammation and ultimately, tumor progression/spread, they are focusing on circulating monocyte populations, which they were not able to assess the our initial study as women were never brought into the lab. The research team is now recruiting newly diagnosed breast cancer patients from their ongoing NCI-funded R01, which focuses on biobehavioral predictors of fatigue in women with early stage breast cancer. To date, they have established relationships with oncologists at UCLA and other practices in the Los Angeles area and have developed procedures for collection and processing of the interview and immune data.

Drs. Bower and Cole are also conducting a more in-depth follow-up with the breast cancer survivors from their earlier study, where participants will undergo an in-person assessment designed to identify the neurobiological mechanisms through which stress influences inflammatory biology. Investigators will collect blood samples for immune analysis, focusing on circulating monocyte populations that have been implicated in tumor progression and enable them to examine the association between lifetime stress exposure, numbers of immature pro-inflammatory monocytes (CD16-/CD14+ leukocytes), circulating markers of inflammation (IL-6, CRP), and monocyte expression of gene transcripts involved in inflammation, chemotaxis, and other biological hallmarks of the pro-inflammatory monocyte subpopulation.

In addition, Drs. Bower and Cole plan to conduct neuroimaging with a subset of these breast cancer survivors, which will enable them to examine the neural mechanisms through which stress may become "embedded" in the brain to influence downstream biological processes, including inflammation. They plan to leverage new findings in this area to elucidate links between stress and inflammation in women with breast cancer.

Bio:
Dr. Steve Cole is one of the world's foremost experts on the molecular pathways by which social and environmental factors influence the activity of human, viral, and tumor genomes. He pioneered the introduction of functional genomics approaches into social and behavioral research, and has provided strategic consulting on that topic to the Institute of Medicine, the National Cancer Institute, the National Institute of Aging, the Santa Fe Institute, and the MacArthur Foundation, among others. He directs the UCLA Social Genomics Core Laboratory and the Molecular Biology Division of the UCLA Norman Cousins Center Inflammatory Biology Core.

Dr. Cole's research uses computational modeling to integrate data from epidemiologic studies, clinical natural history studies, laboratory models, and molecular and biochemical analyses to identify the physiologic signaling pathways that allow social and environmental conditions to influence the molecular pathogenesis of inflammation, infectious diseases, and cancer. Dr. Cole has mapped the molecular pathways by which social factors enhance replication of HIV-1 and HHV-8 viruses, alter expression key immune response genes such as IL-6 and Interferon-beta, and up-regulate expression of pro-metastatic genes by human breast and ovarian cancer cells. His research on social isolation�s effects on leukocyte gene expression was recognized as a Top 100 Science Story in 2007. Dr. Cole�s laboratory also discovered stress-induced plasticity of sympathetic nervous system innervation of the immune system. He has developed a diverse array of computational bioinformatics tools, including Transcript Origin Analysis to identify the cellular sources of differential gene expression and the TELiS transcription factor search engine that will be used to assess the activity of pro- and anti-inflammatory pathways in these studies. Dr. Cole also pioneered the application of that approach to assessing glucocorticoid resistance in vivo. Dr. Cole has extensive experience in DNA microarray analyses of peripheral blood leukocytes, and associated bioinformatics analyses for theory-based testing of genomic hypotheses. He will oversee the analysis and interpretation of DNA microarray data in a BCRF-supported study with Dr. Julienne Bower.