Abstract C024: Lifestyle-associated advanced glycation end products are elevated in ER+ positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention
Authors: Walter Katherine R. , Ford Ford E. , Gregoski Mathew J. , Kramer Rita M. , Knight Kendrea D. , Spruill Laura , Nogueira Lourdes M. , Krisanits Bradley A. , Taylor Marian H. , La Rue Amanda C. , Lilly Michael B. , Ambs Stefan , Chan King , Turner Tonya F. , Varner Heidi , Singh Shweta , Uribarri Jaime , Garrett-Mayer Elizabeth , Armeson Kent E. , Hilton Ebony J. , Clair Mark , Findlay Victoria J. , Peterson Lindsay L. , Magwood Gayenell , Turner David P. 
Published: August 2020

Abstract
Lifestyle factors associated with personal behavior can alter tumor-associated biologic pathways and thereby increase cancer risk, growth and disease recurrence. Advanced glycation end products (AGEs) are reactive metabolites produced endogenously as a byproduct of normal metabolism. A Western lifestyle consisting of high-fat, high-sugar and processed foods as well as little exercise can lead to a significant increase in AGE accumulation in the body and is also associated with driving cancer disparity. Increased AGE accumulation promotes disease phenotypes through modification of the genome, protein crosslinking and dysfunction, and aberrant cell signaling. We evaluated AGE levels in biospecimens from ER+ and ER- breast cancer patients, examined their role in therapy resistance, and assessed the ability of a lifestyle intervention to reduce circulating AGE levels in ER+ breast cancer survivors. A correlation between ER status and AGE levels was observed in tumor and serum samples. AGE treatment of ER+ breast cancer cells impacted pathways associated with ER regulation. We observed a significant increase in phosphorylation of ERalpha following AGE treatment when compared to untreated control with no change in total ERalpha levels. We also observed a significant increase in both AKT and ERK phosphorylation in ER+ cell lines in response to AGE treatment in a time-dependent manner. Inhibition of AKT with Ly294002 and inhibition of ERK with the MEK inhibitor U0126 significantly reduced ERalpha phosphorylation in the presence of AGE. Significantly, ER+ cells treated with AGEs no longer responded to hormonal therapy with tamoxifen. In a proof-of-concept study we examined the ability of a defined exercise and dietary intervention (i.e., cardiac rehabilitation) to reduce circulatory AGE levels in ER+ breast cancer survivors. A significant increase in average very active minutes and average calories burned was observed as a result of the intervention. This was accompanied by a significant reduction in dietary-AGE intake and also showed significant reductions in circulating AGE levels when fasting serum samples were analyzed by ELISA. An analysis of IL6 and CRP levels by ELISA in the same AGE assessed samples revealed no significant differences at any time point. There is a potential prognostic and therapeutic role for lifestyle-derived AGEs in cancer disparity. Given the potential benefits of lifestyle intervention on cancer incidence and mortality, opportunities exist for the development of community health and nutritional programs aimed at reducing AGE exposure in order to improve cancer prevention and treatment outcomes. Lifestyle interventions that lower AGE levels may then be utilized to reduce breast cancer incidence and improve prognosis in cancer disparity populations.
Citation Format: Katherine R. Walter, Ford E. Ford, Mathew J. Gregoski, Rita M. Kramer, Kendrea D. Knight, Laura Spruill, Lourdes M. Nogueira, Bradley A. Krisanits, Marian H. Taylor, Amanda C. La Rue, Michael B. Lilly, Stefan Ambs, King Chan, Tonya F. Turner, Heidi Varner, Shweta Singh, Jaime Uribarri, Elizabeth Garrett-Mayer, Kent E. Armeson, Ebony J. Hilton, Mark Clair, Victoria J. Findlay, Lindsay L. Peterson, Gayenell Magwood, David P. Turner. Lifestyle-associated advanced glycation end products are elevated in ER+ positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C024.