Obesity associated inflammation and postmenopausal breast cancer.
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This proposal outlines a career development plan to help Dr. Erin Giles complete her postdoctoral training and establish an independent research program focused on obesity and postmenopausal breast cancer. Her mentored training will be conducted in a multidisciplinary group of scientists with research expertise in breast cancer, metabolism, menopause, and immunology. Her mentors, Drs. MacLean and Schedin, are well-funded scientists with established collaborations focused on obesity and postmenopausal breast cancer. Their extensive experience with trainees will be complemented by those in her advisory team, Drs. Van Pelt, Thor, Anderson, and Regensteiner. Collectively, this team will provide an outstanding training environment that will allow her to fill critical gaps in her toolbox and knowledge base that will enhance her ability to study inflammation and the tumor microenvironment, and provide her with the ability to conduct clinical research studies. During the training phase of this award, she will strengthen her scholarly activities, establish importantcollaborations, and acquire critical data and samples that will ensure her successful transition.toindependence Rationale: Despite the known link between obesity and postmenopausal breast cancer, the mechanisms underlying this association are not completely understood. The working hypothesis that will be examined in this proposal is that adipose tissue inflammation mediates the adverse effects of obesity on breast cancer after menopause and that this effect involves the general recruitment of macrophages to adipose tissues by obesity and the promotion of an M2 phenotype by tumors. Design: Dr. Giles will utilize bone derived macrophages, adipose tissues, and human breast cancer cells in co- culture systems to characterize the interactions that create a tumor promoting environment. She will employ a well-established preclinical model to determine whether anti-inflammatory agents (ibuprofen) and interventions (caloric restriction or exercise) can inhibit the inflammatory response and tumor promotion that occurs with the loss of ovarian function. She will extend these studies with a medically-induced model of menopause to determine if exercise has similar effects in humans. The cumulative effect of this carefully developed training and research program will: 1) further our understanding of the role of inflammation in promoting tumor growth in the obese; 2) result in the submission of a highly competitive R01; and 3) launch the PI''s independent research career bridging the fields of breast cancer, metabolism, and inflammation. Relevance: Untangling the interrelationship between obesity, menopause, weight gain and inflammation, and their combined effects on tumor progression, could facilitate design of novel therapies for treatment/prevention of cancer. Use of anti-inflammatory agents, in conjunction with standard obesity treatments like as caloric restriction or exercise, has the potential to reduce obesity-associated risk and improve clinical outcomes.