Advanced glycation end products are elevated in estrogen receptor-positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention

K Walter ,Michael B Lilly,Van Phan,David P Turner,Gayenell Magwood,Kent Armeson ,Kenneth R Knight ,Elizabeth Garrett‐Mayer ,Rita Kramer ,K K Chan ,Ebony J Hilton,Amanda C La Rue,Shweta Singh,Lourdes M Nogueira,Mark J Clair,Stefan Ambs,Laura Spruill,Marvella E Ford,Andrea M Abbott,Victoria J Findlay,Lindsay L Peterson,Mathew J Gregoski,Heidi Varner,Bradley A Krisanits,Jaime Uribarri,Tonya F Turner,Marian H Taylor

doi:10.1007/s10549-018-4992-7

Abstract

PurposeLifestyle 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.MethodsWe 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.ResultsAn 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.ConclusionsThere 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.

Highlights

Breast cancer is the 2nd leading cause of new cancer cases in the US, where more than 3 million breast cancer survivors reside
Given the common signaling cascades involved in Advanced glycation end products (AGEs) pathogenesis and ERα regulation, we examined the ability of AGEs to augment ERα phosphorylation and tamoxifen resistance, and tested the ability of a defined lifestyle intervention program to lower AGE levels in overweight/obese post-menopausal women with non-metastatic stage I–III ER+ breast cancer
Pharmacological targeting of the MAPK/ERK and PI3K/AKT pathways in the presence of AGE was achieved in serum-free media using the molecular inhibitors U0126 (ERK) and LY294002 (AKT) (Cell signaling Technology, Danvers, MA) at a concentration of 10uM for 12 h before exposure to AGE metabolites

Summary

Introduction

Breast cancer is the 2nd leading cause of new cancer cases in the US, where more than 3 million breast cancer survivors reside. Lifestyle behaviors such as an unhealthy diet and physical inactivity are modifiable prognostic factors that may have distinct molecular consequences on breast cancer outcomes. AGEs irreversibly accumulate in our tissues causing pathogenic effects on organ homeostasis, genetic fidelity, protein function, and cell signaling cascades [1,2,3]. Increases in the AGE accumulation pool lead to the perpetual activation of cancer-associated cell signaling cascades including MAPK (mitogen-activated protein kinase) and AKT (protein kinase B) leading to aberrant transcriptional activity, immune function, and oxidative stresses [7]

Methods

Results

Conclusion