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Suzanne Conzen, MD

Chronic stress, the endocrine response, and breast cancer biology (Conzen Lab)

For many decades, identifying neuroendocrine mechanisms linking psychosocial factors (e.g. chronic stressors) to human disease has been the subject of intense interest by both social and biological scientists. Together, the endocrine, autonomic nervous and immune systems comprise an individual’s physiological response to both chronic and acute social stressors; these systems also mediate signaling pathways and gene expression changes at the cellular level that have the potential to alter tumor biology. However, it is only recently that the detailed molecular components connecting biopsychological stressors, the endocrine response, and cancer biology have begun to be uncovered. Both the glucocorticoid stress hormones and the adrenergic systems can induce tumor cell survival mechanisms and alter cell proliferation, tumor invasion, and angiogenesis. In addition, these signals affect inflammatory and metabolic tissues that modulate tumor growth through systemic and microenvironment effects. Assessing the precise mechanisms of these interactions requires an appreciation of the subtleties of measuring the social environment, the individual’s behavioral and neuroendocrine response, as well as the tumor and its environment.

Together with the McClintock laboratory at the University of Chicago’s Institute of Mind and Biology, we have developed a model of social isolation as it pertains to a transgenic model of human breast cancer (SV40Tag) and a Sprague-Dawley female rat model of spontaneous mammary gland cancer. In both models, we found that chronic social isolation reduces exploratory behavior in a novel environment as well as heightening the corticosterone response to an acute restraint stressor. In the SV40 Tag transgenic model, we examined gene expression differences in the mammary glands of isolated versus grouped female mice prior to invasive tumor development and uncovered a significant increase in lipid synthesis and glycolytic pathway genes, suggesting an association of the social environment with cancer-promoting metabolic changes. Interestingly, many of these changes in gene expression appear most significant in the adipocyte fraction of the mammary gland. For example, the increased expression of the key metabolic genes Acaca, Hk2, and Acly, initially observed in the whole mammary gland, was found to be significantly elevated only in the adipocyte fraction. Furthermore, in collaboration with Dr. Matthew Brady, we found that metabolic gene expression was not consistently increased in the visceral fat of social isolates. These results suggest that exposure to chronic social isolation results in mammary fat depot-specific metabolic gene expression changes, followed by increased growth of invasive tumors. Understanding the specific mechanisms that confer increased estrogen independent mammary tumor growth in association through changes in mammary fat metabolism is the current focus of our collaboration with Dr. Brady and other members of the Diabetes Center.

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