Stephen D. Hursting, PhD, MPH

2009-2010 BCRF Project:
The evidence that obesity adversely affects women's health, including increasing the risk of breast cancer in postmenopausal women, is overwhelming and indisputable. Obesity is also associated with poor prognosis of breast cancer in both pre- and postmenopausal women. The prevalence of obesity among adolescents and middle-aged women has rapidly increased over the past three decades; thus, the harmful impact of obesity on breast cancer will continue to rise as many of these women approach their postmenopausal years. However, the specific mechanisms by which obesity affects breast cancer risk or prognosis are not clearly understood, and strategies for offsetting the negative effects of obesity are urgently needed.

Dr. Hursting's previous BCRF-funded work in a Wnt-1 transgenic model of postmenopausal breast cancer established that obesity increases mammary tumor development, at least in part by increasing growth factor levels and activating the IGF-1/Akt/mTOR signaling pathway. The researchers have now also established that obesity enhances resistance to endocrine therapy, such as tamoxifen, in the Wnt-1 model. The studies in progress, which will be completed in September, are designed to test the hypothesis that pharmacologic inhibition of the IGF-1/Akt/mTOR pathway preserves the responsiveness to the chemopreventive effects of tamoxifen in erbB2 transgenic models (an established model for studying the transition from estrogen receptor-positive to estrogen receptor-negative breast cancer). A finding that mTOR inhibition prevents tamoxifen resistance in obese models could significantly impact breast cancer prevention strategies in obese women.

Mid-Year Progress Report:
Dr. Hursting's team has completed an initial study, which indicates that their model is not responsive to the aromatase inhibitor letrozole at any level of adiposity. However, they did find that obesity enhances mammary tumor development in their model, and of particular importance, weight loss in obese laboratory models did not reverse the adverse effects of obesity in this model. Interestingly, the mTOR inhibitors Rad001 and rapamycin both reduced tumor growth regardless of adiposity level, and importantly, reversed the adverse effects of obesity or former obesity.

The researchers are currently hard at work to understand the mechanisms underlying the persistence of the adverse effects of obesity after weight loss, and are also uncovering novel metabolic effects of the mTOR inhibitors that might explain some of their protective effects independent of mTOR inhibition. Successful accomplishment of the proposed aims will provide a strong foundation for future translational studies, including a planned intervention study in postmenopausal women.

Bio:
Dr. Stephen D. Hursting is Professor and Chair of the Department of Nutritional Sciences, as well as the Margaret McKean-Love Chair of Nutritional, Molecular and Cellular Sciences, at the University of Texas at Austin. He is also Professor of Carcinogenesis at the UT-MD Anderson Cancer Center. Dr. Hursting earned his PhD in nutritional biochemistry and MPH in nutritional epidemiology from the University of North Carolina at Chapel Hill, and he completed postdoctoral training in molecular carcinogenesis and cancer prevention as a Cancer Prevention Fellow at the NCI. Prior to joining the University of Texas faculty, Dr. Hursting was Chief of the NCI's Nutrition and Molecular Carcinogenesis Laboratory Section and Deputy Director of the NCI's Office of Preventive Oncology (1999-2005).

Dr. Hursting's research interests center on diet-gene interactions relevant to cancer prevention, particularly the molecular and hormonal mechanisms underlying energy balance-breast cancer associations. His research program, which has resulted in more than 125 peer-reviewed publications, focuses on three interrelated areas: 1. mechanism-based nutrition and cancer prevention studies in genetically engineered mice; 2) molecular and metabolic mechanisms underlying the energy balance and carcinogenesis relationship, with a particular interest in the roles of the IGF-1/Akt/mTOR signaling pathways and inflammatory pathways in breast and pancreatic cancers; and 3) translational nutrition and chemoprevention studies linking preclinical research with complementary clinical or epidemiologic studies.