A multi-informative, multi-level approach to understanding the role of stress in breast cancer disparities

CN05-01 The University of Chicago’s Center for Interdisciplinary Health Disparities Research (CIHDR) is one of the eight centers (P50) funded through NIH’s Population Health and Health Disparities initiative. The trandisciplinary team of social, behavioral, and biological/genetic investigators is united by a central question: Why, despite the fact that white women are more likely to develop breast cancer, are African-American women more likely to die from it? Based on the knowledge that breast cancer develops only after a series of complex genetic interactions, CIHDR investigators designed four mutually-informative, interdependent research projects to determine the causal links between these genetic mechanisms and the social circumstances and neighborhoods of some African-American women. Investigators from inside and outside the university, as well as members of the community who are especially vulnerable to adverse health conditions, contribute to CIHDR’s scientific agenda. Taking a multi-informative, multi-level approach, CIHDR’s goal is to move beyond correlations to identify causal steps that start with a person’s reaction to his or her social and physical environment and resulting psychological states, which in turn become embodied by specific endocrine, immune, and neural events that regulate apoptosis, as well as the function of genes that both promote and inhibit carcinogenesis. Two of CIHDR’s four research projects, led by Drs. Funmi Olopade and Sarah Gehlert, work with the same group of 230 newly-diagnosed African-American women living on Chicago’s South Side. These projects guide and receive guidance from two projects that employ animal models (led by Drs. Suzanne Conzen and Martha McClintock). These animal models enable laboratory animal manipulations to establish causation, as determined by biopsychologists, molecular biologists, pathologists, and geneticists. In both human and animal research, CIHDR focuses on measuring a range of environments that create daily stressors (e.g., high-crime neighborhoods) or ameliorate them (e.g., neighborhood resources), as well as the lack or presence of desired social support in the face of these stressors. Psychological measures include vigilance, anxiety, loneliness, and depression. All studies measure tumor stage and grade, receptor status for stress, and reproductive hormones, apoptotic mechanisms, and hyper-methylation in the promoter region of hormone receptors. Among the key findings to date: Work with animal models suggests that the natural variation in the glucocorticoid response to a stressor predicts the timing of mammary tumorigenesis. Researchers focus on the regulation of the glucocorticoid system since it:(a) is modulated by psychological and social conditions,and (b) suppresses apoptosis in breast cancer cells, allowing microscopic lesions to grow to a palpable volume. The activation of glucocorticoid receptors initiates a downstream signaling pathway that ultimately results in cell survival through suppression of apoptosis. Thus, higher reactivity to stress may predict earlier tumor development through heightened secretion of glucocorticoids. The study tested this hypothesis by subjecting all animals to the same physical restraint stressor and steadily monitoring the development of spontaneous mammary tumors. High glucocorticoid reactivity to a stressor was found to be associated with earlier tumor development. Analysis of breast cancer gene expression profiles in a cohort of African-American and white women revealed no “race-specific” gene expression. CIHDR has made substantial progress in characterizing mammary cancers suffered by African-American women. Self-reported African-American women were found to have a higher proportion of tumors within the basal-like (triple negative or ER-/PR-/HER2-nega-tive tumors) and unclassified “intrinsic gene expression” subtypes. These tumors do not depend on estrogen and therefore will not respond to hormonal therapy such as tamoxifen or aromatase inhibitor, leaving chemotherapy as the only available treatment option. In a study comparing breast cancers from Nigeria, Senegal, and North America, researchers found that women of African ancestry are more likely to be diagnosed with triple negative and unclassified breast cancer. The study found a high rate ofBRCA1 promoter methylation in breast cancers characterized by the so-called triple negative(ER/PR/HE2) tumors from the United States and Nigeria. To date about 30% of tumors from Nigeria and 20% of tumors from African-American women exhibit BRCA1promoter methylation. Researchers have also identified statistically significant links along a downward causal pathway between the population and disease levels in humans. These links are between neighborhood/community-level factors (e.g., violent crime), psychosocial responses (sexual assault, social isolation, vigilance, and depression), and cortisol response. CIHDR’s human work builds on the animal models by examining the connections between the social environment, psychosocial processes, and biological processes in African-American women living on Chicago’s South Side who were newly diagnosed with breast cancer living. This study involved the development of a Built Environment Team, which measured features in the four-block area around women’s homes that might either impede or enhance social interactions (e.g., vacant buildings and lots) and collected data on violent crime, collective efficacy, socioeconomic indicators, and other elements in the vicinity of women’s homes. The study found that social isolation, vigilance, and depression were highly correlated and represent facets of a “psychosocial suite” that demonstrates how the social environment gets “under the skin” to alter the body’s ability to repair cells. CIHDR’s research to date suggests that stress-signaling pathways may be tumorigenic and that women exposed to social isolation require screening at a younger age than is currently recommended. Prevention agents against breast carcinomas may include inhibitors of glucocorticoid signaling. In addition, understanding the suite of psychosocial factors that contribute to a woman’s vulnerability to stress and development of breast cancers can help treatment providers identify high-risk individuals and thus allow resources to be maximized. CIHDR researchers are better able to contribute to cancer detection, prevention, and treatment through additional resources leveraged through the entire CPHHD initiative. Based on CIHDR investigations, researchers have successfully competed for a Specialized Program of Research Excellence (SPORE) in Breast Cancer. Several of the SPORE projects will translate advances in breast imaging, genetics, and drug development to the benefit of patients with triple negative disease. CIHDR uses knowledge gained from this work to develop better tools for risk assessment, prevention, early detection, and treatment of breast cancer among African-American women.