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

Abstract

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.

Keywords: Advanced glycation end product; Breast cancer; Estrogen receptor; Lifestyle intervention; Tamoxifen resistance.

Fig. 1

AGE levels are elevated in ER+ breast cancer patients. a Quantification of epithelial AGE levels in breast normal and tumor tissue using IHC staining. b Quantification of stromal AGE levels in breast tumor tissue using IHC staining. c Quantification of circulating AGE levels, analyzed by ELISA, in serum from breast cancer patients stratified by well and poorly differentiated tumors. d Quantification of circulating AGE levels, analyzed by ELISA in serum from breast cancer patients stratified by ER status. e Quantification of CML levels in non-cancer and breast tumor tissue using LC/MS/MS. f Quantification of CEL levels in non-cancer and breast tumor tissue using LC/MS/MS. g Quantification of CML levels, analyzed by LC/MS/MS in non-cancer and breast tumor tissue stratified by ER status. h Quantification of CEL levels, analyzed by LC/MS/MS in non-cancer and breast tumor tissue stratified by ER status

Fig. 2

AGE treatment activates pathways associated with ER regulation and tamoxifen treatment. a Western blot analysis of time-dependent AKT and ERK phosphorylation after treatment with AGE (50ug/mL) in MCF7 breast cancer cells. b Western blot analysis of ERα phosphorylation after treatment with AGE (50ug/mL) in MCF7 breast cancer cells. c Western blot analysis of AKT and ERK phosphorylation after treatment with AGE (50ug/mL) in MCF7 cells in the presence of AKT inhibitor. d Western blot analysis of AKT and ERK phosphorylation after treatment with AGE (50ug/mL) in MCF7 cells in the presence of ERK inhibitor. e Cytotoxicity assay of MCF7 cell proliferation after treatment with tamoxifen (10uM) in the presence of increasing AGE concentration. f Cytotoxicity assay of MCF7 cell proliferation after treatment with tamoxifen (20 μM) in the presence of increasing AGE concentration

Fig. 3

Lifestyle intervention reduces dietary-AGE intake in ER+ breast cancer survivors. a Conceptual Framework for the PA and dietary intervention. b Average very active minutes achieved by participants during the 11-week lifestyle intervention as assessed from Fitbit data. c Average calories burned by participants during the 11-week lifestyle intervention as assessed using 7-day food records. d Calorie intake for each participant as assessed using 7-day food records. e Average VO2 max at baseline and completion of the 11-week lifestyle intervention. f Dietary-AGE intake per participant at baseline, week 8, and week 11 of the lifestyle intervention as assessed using 7-day food records

Fig. 4

Lifestyle intervention reduces the levels of AGE in the circulation of ER+ breast cancer survivors. a Circulatory AGE levels per participant at baseline, week 8 and week 11 of the lifestyle intervention as assessed by ELISA. b Average AGE levels at baseline, weeks 8 and 11 for all participants of the lifestyle intervention as assessed by ELISA. c Percent change in circulating AGE levels at baseline, weeks 8 and 11 for all participants at of the lifestyle intervention and 13 weeks after the intervention had ended as assessed by ELISA. d Average IL6 levels at baseline and at completion for all participants of the 11-week lifestyle intervention as assessed by ELISA. e Average CRP levels at baseline and at completion for all participants of the 11-week lifestyle intervention as assessed by ELISA