Purpose Lifestyle factors associated with personal behavior can alter tumor-associated biological pathways and thereby increase cancer risk, growth, and disease recurrence. Advanced glycation end products (AGEs) are reactive metabolites produced endogenously as a by-product of normal metabolism. A Western lifestyle also promotes AGE accumulation in the body which is associated with disease phenotypes through modification of the genome, protein crosslinking/dysfunction, and aberrant cell signaling. Given the links between lifestyle, AGEs, and disease, we examined the association between dietary-AGEs and breast cancer. Methods We evaluated AGE levels in bio-specimens from estrogen receptor-positive (ER+) and estrogen receptor-negative (ER−) breast cancer patients, examined their role in therapy resistance, and assessed the ability of lifestyle intervention to reduce circulating AGE levels in ER+ breast cancer survivors. Results An association between ER status and AGE levels was observed in tumor and serum samples. AGE treatment of ER+ breast cancer cells altered ERα phosphorylation and promoted resistance to tamoxifen therapy. In a proof of concept study, physical activity and dietary intervention was shown to be viable options for reducing circulating AGE levels in breast cancer survivors. Conclusions There is a potential prognostic and therapeutic role for lifestyle derived AGEs in breast cancer. Given the potential benefits of lifestyle intervention on incidence and mortality, opportunities exist for the development of community health and nutritional programs aimed at reducing AGE exposure in order to improve breast cancer prevention and treatment outcomes. Electronic supplementary material The online version of this article (10.1007/s10549-018-4992-7) contains supplementary material, which is available to authorized users.

Bệnh mạch vành cấp (MVC) là một biến chứng chủ yếu, hay gặp và thường dẫn đến tử vong ở các bệnh nhân đái tháo đường type 2 (ĐTĐT2). Nguyên nhân là do bệnh nhân ĐTĐT2 có những yếu tố làm tăng nguy cơ bị MVC như: mỡ máu cao; huyết áp cao; béo phì và thói quen ít vận động. Bệnh ĐTĐT2 với biến chứng MVC có thể làm sai hỏng cấu trúc và chức năng của tim dẫn tới loạn nhịp tim và suy tim. Vì vậy, việc nghiên cứu để hạn chế các biến chứng MVC ở các bệnh nhân ĐTĐT2 sẽ làm giảm nguy cơ tử vong và kéo dài cuộc sống cho họ. Trong nghiên cứu này, phương pháp biến tính nhiệt đã được sử dụng để loại bỏ các protein hàm lượng lớn trong huyết thanh bệnh nhân ĐTĐT2_MVC. Hỗn hợp protein sau khi phân đoạn nhiệt được phân tách bằng điện di hai chiều và hình ảnh điện di được xử lý bằng phần mềm PDQuest v7.1. Những protein có mức độ biểu sai khác có ý nghĩa giữa mẫu thường và mẫu bệnh sẽ được nhận dạng bằng sắc ký lỏng kết nối khối phổ (nanoLC-MS/MS). Kết quả, 13 protein có mức độ biểu hiện tăng/giảm trong huyết thanh của bệnh nhân ĐTĐT2_MVC đã được xác định. Trong đó, 5 protein (chuỗi fibrinogen alpha, chuỗi fibrinogen gama, chuỗi haptoglobin beta, chuỗi haptoglobin alpha 1 và zinc alpha 2 glycoprotein) có mức độ biểu hiện tăng và 6 protein (alpha 1 antitrypsin, angiotensinogen, antithrombin III, apolipoprotein A-I, apolipoprotein E và transthyretin) có mức độ biểu hiện giảm trong huyết thanh bệnh nhân ĐTĐT2_MVC. Trong khi đó chuỗi haptoglobin alpha 2 và apolipoprotein A-IV lúc biểu hiện tăng, lúc biểu hiện giảm trong huyết thanh mẫu bệnh. Kết quả nghiên cứu của chúng tôi cho thấy các protein này đều liên quan đến sự phát sinh và phát triển của bệnh ĐTĐT2 và bệnh MVC. Từ khóa: Bệnh mạch vành cấp, đái tháo đường type 2, điện di hai chiều, huyết thanh, protein bền nhiệt, sắc ký lỏng kết nối khối phổ.

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.