Abstract C65: Defining the implications of sugar derived metabolites (AGEs) to tamoxifen resistance and breast cancer disparity: Is it a question of lifestyle?

Abstract

Tamoxifen is the most widely prescribed adjuvant therapy for estrogen receptor positive (ER+) breast cancer which comprises around 70% of all breast cancer cases. While many patients respond positively to tamoxifen treatment around 50% have de-novo resistance and approximately 30% of responsive tumors recur due to acquired drug resistance. Compared to European American women, African-American women with ER+ breast cancer, have worse progression-free and overall survival which coincides with increased resistance to anti-cancer therapies such as tamoxifen. Poor diet, low income, obesity and a lack of exercise are established lifestyle factors that are known to increase cancer burden and are often more prevalent in African American communities. Our research has identified a potential mechanistic link between sugar derived metabolites and estrogen receptor (ER) phosphorylation which provides a biological consequence of these established lifestyle factors which may directly impact tamoxifen therapy and minority health. Glycation is the non-enzymatic glycosylation of sugar moieties to biological macromolecules such as protein and DNA which produces reactive metabolites known as advanced glycation end products (AGE's). AGE's accumulate in our tissues as we grow older and drive many of the complications associated with diseases displaying health disparity including diabetes, metabolic syndrome, Alzheimer's and heart disease. Significantly, low income, obesity and an inactive lifestyle are established factors driving health disparity that also contribute to increased AGE accumulation levels in our bodies. In particular, AGE content in the Western Diet has consistently increased over the last 50 years due to increased consumption of sugar laden and cheap processed/manufactured foods which are high in reactive AGE metabolites and promote obesity. Due to the established links with lifestyle and cancer disparity we examined the biological effects of AGEs on tamoxifen therapy and found that elevated AGE levels can directly affect the response to tamoxifen treatment and promote tamoxifen resistance. AGE treatment in ER+ breast cancer cell models promoted tamoxifen resistance via the activation of the MAPK and AKT pathways leading to resistance associated changes in ERα phosphorylation. We also observed greater levels of AGE and its cognate receptor for AGE (RAGE) within breast cancer tumor and serum samples and showed a correlation between tumor progression and intra-tumoral AGE concentration. Strategies to eliminate or delay the occurrence of tamoxifen resistance would contribute to increasing overall survival in minority populations. By associating lifestyle-derived AGEs with tamoxifen resistance, opportunities exist for impacting cancer treatment initiatives arising through health and nutritional education and community outreach programs driven by basic, translational, epidemiological and cancer prevention research initiatives. Citation Format: Katherine R. Walter, Danzell M. Smith, Van Phan, Laura spruill, Marvella E. Ford, Victoria J. Findlay, David P. Turner. Defining the implications of sugar derived metabolites (AGEs) to tamoxifen resistance and breast cancer disparity: Is it a question of lifestyle? [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C65.