Program Official

Principal Investigator

Paul S
Awardee Organization

University Of Colorado Denver
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Novel dietary interventions for reducing obesity-associated breast cancer

Despite new treatment modalities, the incidence of breast cancer has remained steady in recent years with >250,000 new diagnoses and >40,000 deaths annually in the US. Concurrently, the proportion of US women with overweight or obesity continues to rise, and is approaching 70%. Obesity and metabolic disease (which occurs in lean and obese women) increase breast cancer incidence and worsen patient outcomes in women of all ages. Premenopausal women with obesity are at increased risk of triple negative (TN) breast cancer (lacking any targetable factors). Postmenopausal women with obesity incur more estrogen receptor (ER) positive breast cancer and are more likely to develop resistance to endocrine therapies. While estrogen is clearly an important part of this relationship, two key observations suggest that there may be estrogen-independent mechanisms at play: 1) obesity is accompanied by worse prognosis for estrogen-independent triple negative breast cancer; and 2) anti-estrogen therapies are less effective against ER+ breast tumors in women with obesity. Regardless of tumor subtype and menopausal status, excess weight is associated with poor outcomes for breast cancer patients. Weight loss is known to improve breast cancer outcomes, but most people cannot sustain the standard dietary weight loss strategies and weight regain is common. Intermittent energy restriction (IER) is a novel dietary weight loss strategy that may have more beneficial effects on metabolic health and on breast cancer risk and tumor progression. The work in this proposal will employ preclinical, clinical, and interventional studies, to examine a novel mechanism of obesity-associated tumor progression and the value and feasibility of innovative dietary interventions for eliminating obesity’s adverse effects on breast cancer. We have merged expertise in nutrition, obesity, and medical oncology to: 1) examine a novel role that cancerassociated fibroblasts (CAFs) and the tumor microenvironment (TME) may be playing in obesity-associated tumor progression; 2) investigate if the novel dietary weight loss strategy of IER can eliminate obesity-associated tumor progression; and 3) perform an ORBIT Phase IIa proof-of-concept study examining the ability of an IERbased weight loss intervention to reach meaningful clinical milestones in breast cancer patients afflicted with overweight and obesity and refine the intervention for delivery in a future randomized efficacy trial. If the objectives of this proposal are achieved, we will have: * Advanced our understanding of the obesity – breast cancer relationship, with evidence of a novel role for CAFs and the TME in obesity-associated tumor promotion for TN and ER+ breast cancer; * Established the foundation for IER weight loss trials in breast cancer survivors, with data that will help us adapt these strategies to the unique characteristics and needs of this patient population; and * Identified novel circulating biomarkers of a pro-metastatic TME, which may help identify patients most susceptible to metastatic disease.


  • Hill EB, Siebert JC, Yazza DN, Ostendorf DM, Bing K, Wayland L, Scorsone JJ, Bessesen DH, MacLean PS, Melanson EL, Catenacci VA, Borengasser SJ. Proteomics, dietary intake, and changes in cardiometabolic health within a behavioral weight-loss intervention: A pilot study. Obesity (Silver Spring, Md.). 2022 Nov;30(11):2134-2145. PMID: 36321274
  • Ward AV, Matthews SB, Fettig LM, Riley D, Finlay-Schultz J, Paul KV, Jackman M, Kabos P, MacLean PS, Sartorius CA. Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism. Cancers. 2022 Mar 31;14. (7). PMID: 35406548
  • Wellberg EA, Corleto KA, Checkley LA, Jindal S, Johnson G, Higgins JA, Obeid S, Anderson SM, Thor AD, Schedin PJ, MacLean PS, Giles ED. Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer. Breast cancer research : BCR. 2022 Jun 20;24(1):42. PMID: 35725493