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.

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Highlights Nutrition associated glycoxidation promotes aggressive prostate tumor growth. AGEs, the final product of glycoxidation were a key pro-tumorigenic effector. Dietary-AGE mediated effects were dependent upon stromal RAGE expression. AGE-RAGE signaling caused a regulatory program of activated stroma & CAF activation. Dietary-AGE effects were reproduced using in vivo, ex vivo and in vitro models.

Objectives The literature regarding the role of advanced glycation end products (AGEs) on tumor biology has shown only moderate promise reflected by increases in cell growth, migration and invasion in vitro which is not supported by increased tumor growth in vivo14-16– A caveat to these studies is that they are centered upon a single AGE peptide and a subsequent assessment of their molecular effects on tumor epithelial cells. The objective is to show that by feeding mice a high AGE diet we can recapitulate a microenvironment comprising of a wide spectrum of AGEs which can influence neoplastic growth. Methods We recapitulated a dietary-AGE induced microenvironment in syngeneic xenograft and spontaneous breast and prostate mouse cancer models and the effects on tumor growth assessed. The mechanistic consequences of dietary-AGEs on the tumor microenvironment were further defined using mouse and human primary and immortalized two-compartment co-culture ex vivo culture models. Results Dietary-AGE consumption in breast and prostate tumor models significantly accelerated tumor growth by functioning as ligand to the transmembrane receptor for AGE (RAGE). Our studies demonstrate that AGEs promote neoplastic growth by functioning as ligand to RAGE expressed in the tumor stroma not the tumor epithelial cells. Dietary-AGE activation of RAGE in both breast and prostate tumors caused a regulatory program of ‘activated fibroblasts’ defined by increased expression of cancer associated fibroblast markers, NFkB and MYC upregulation, and pro-tumorigenic paracrine secretion. Complementary to this, our published studies show that high intake of dietary AGE after BCa diagnosis increases risk of mortality in postmenopausal women. Conclusions These data demonstrate, for the first time, the oncogenic potential of dietary-AGEs in promoting neoplastic growth. This lays the foundation for strategic changes aimed at reducing cancer incidence and mortality as pharmacological, educational and/or interventional strategies aimed at reducing the dietary-AGE accumulation pool may one day be viewed as universal cancer preventative and/or therapeutic initiatives especially when combined with existing therapies. Funding Sources David P. Turner was supported by grants from the NIH/NCI, R21 CA194469 and U54 CA21096..