This project tests a novel hypothesis regarding the emergence of obesity-associated risk for breast cancer after menopause, while examining the impact of two relevant interventions targeting metabolic control, metformin and regular exercise, on obesity-associated tumor promotion. The hypothesis asserts that obesity- associated impaired metabolic regulation establishes a susceptibility to the tumor promoting effects of the menopause-induced weight gain. Based upon this hypothesis, both impaired metabolic regulation and the positive energy imbalance are required for the emergence of obesity-associated breast cancer risk after menopause. Three well-characterized models of breast cancer (methylnitrosourea), obesity (obesity-prone rats) and menopause (surgical ovariectomy, OVX) were merged to create an experimental paradigm for studying obesity-associated tumor promotion after menopause. In response to OVX, lean and obese, tumor bearing rats exhibit a period of rapid weight gain, during which obese rats have fewer tumors regress, more tumors progress, and more tumors newly emerge. The slower, less energetically efficient weight gain of obese rats predicts post-OVX tumor burden and multiplicity, and metformin therapy dramatically suppresses tumor progression after OVX. Tumors in the obese have increased expression of progesterone receptor (PR) prior to OVX, and during OVX-induced weight gain. In the first aim, we test the dual-requirement hypothesis by manipulating metabolic control and energy balance during the critical window of OVX-induced weight gain. Two relevant interventions known to improve metabolic control (metformin, regular exercise) will be employed transiently during the narrow window of OVX- induced weight gain, to assess their impact on long term tumor outcomes. In the second aim, we employ a 24-hr multi-tracer study of energy balance and fuel utilization to examine if obesity impairs the metabolic response to OVX-induced overfeeding and imparts an """"""""aggressive"""""""" glycolytic/lipogenic phenotype in tumors. We will examine if metformin therapy normalizes this metabolic response and ameliorates the effects of obesity on tumor metabolism. In the third aim, we investigate the cause and consequences of the obesity-associated elevation in PR expression. Tissues from aim 2 will be used to determine if estrogens are increased locally in the mammary gland in response to overfeeding during OVX-induced weight gain. Human breast cancer cells that do (PR+) and do not (PR-) express PR will be used to examine the ligand-independent effects of PR expression on tumor cell metabolism and proliferation, when challenged with a nutrient-rich or cytokine-rich environment. Together, these studies will examine if poor metabolic control and pre-existing tumor receptor status converge to promote survival and growth after the loss of ovarian function. Observations in this project may point to a critical window of time in peri-menopause or shortly after menopause that will maximize the prevention and therapeutic efficacy of interventions that that improve insulin sensitivity and/or metabolic control.

Public Health Relevance

Obesity now affects over two-thirds of the US population, and it significantly increases the risk for breast cancer after menopause. The present study tests the hypothesis that both impaired metabolism and a positive energy imbalance are critical for the emergence of obesity related risk after menopause. Observations from this study may point to a critical window of time after menopause that will maximize the prevention and therapeutic efficacy of interventions targeting metabolic control, like metformin and regular exercise.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemo/Dietary Prevention Study Section (CDP)
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Ross, Sharon A
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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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
MacLean, Paul S; Blundell, John E; Mennella, Julie A et al. (2017) Biological control of appetite: A daunting complexity. Obesity (Silver Spring) 25 Suppl 1:S8-S16
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; Hagman, Jennifer; Pan, Zhaoxing et al. (2016) Weight restoration on a high carbohydrate refeeding diet promotes rapid weight regain and hepatic lipid accumulation in female anorexic rats. Nutr Metab (Lond) 13:18
Giles, Erin D; Jackman, Matthew R; MacLean, Paul S (2016) Modeling Diet-Induced Obesity with Obesity-Prone Rats: Implications for Studies in Females. Front Nutr 3:50
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
Fornetti, J; Flanders, K C; Henson, P M et al. (2016) Mammary epithelial cell phagocytosis downstream of TGF-?3 is characterized by adherens junction reorganization. Cell Death Differ 23:185-96
Sladek, Celia D; Stevens, Wanida; Song, Zhilin et al. (2016) The ""metabolic sensor"" function of rat supraoptic oxytocin and vasopressin neurons is attenuated during lactation but not in diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 310:R337-45

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