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 important collaborations, and acquire critical data and samples that will ensure her successful transition.to independence 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.
Obesity increases the incidence, progression, and eventual mortality from breast cancer in postmenopausal women, yet the mechanisms that underlie this relationship remain poorly understood. Our lab has found that weight gain during the menopausal window plays a critical role in tumor promotion, and in this study we will investigate how the inflammatory response to this weight gain is involved. Identifying inflammatory changes that promote breast cancer during this time will permit the rational design of therapies targeting inflammation. By combining traditional cancer therapies with agents directed at inflammation and other obesity-related targets, we hope to significantly contribute to the control of obesity-related breast cancer. The written critiques of individual reviewers are provided in essentially unedited form in this section. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.
|Giles, Erin D; Jindal, Sonali; Wellberg, Elizabeth A et al. (2018) Metformin inhibits stromal aromatase expression and tumor progression in a rodent model of postmenopausal breast cancer. Breast Cancer Res 20:50|
|Foright, R M; Presby, D M; Sherk, V D et al. (2018) Is regular exercise an effective strategy for weight loss maintenance? Physiol Behav 188:86-93|
|Checkley, L Allyson; Rudolph, Michael C; Wellberg, Elizabeth A et al. (2017) Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor RegressionIn Vivo. Cancer Prev Res (Phila) 10:198-207|
|Sherk, Vanessa D; Jackman, Matthew R; Giles, Erin D et al. (2017) Prior weight loss exacerbates the biological drive to gain weight after the loss of ovarian function. Physiol Rep 5:|
|Wellberg, Elizabeth A; Checkley, L Allyson; Giles, Erin D et al. (2017) The Androgen Receptor Supports Tumor Progression After the Loss of Ovarian Function in a Preclinical Model of Obesity and Breast Cancer. Horm Cancer 8:269-285|
|Giles, Erin D; Steig, Amy J; Jackman, Matthew R et al. (2016) Exercise Decreases Lipogenic Gene Expression in Adipose Tissue and Alters Adipocyte Cellularity during Weight Regain After Weight Loss. Front Physiol 7:32|