Advanced glycation end products are elevated in estrogen receptor-positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention.
Impact factor: 3.940
Level of evidence: IV
Intro: A mechanistic link between AGEs and ERa regulation and how poor diet and lifestyle may directly impact tamoxifen efficacy was identified in this study.
Methods: microarray, western blot, ELISA, cytotoxic assay.
Results: The data shows that in breast tumors, AGE levels are higher in carcinoma tissue than in hyperplasia (p=0.03) and non-cancer tissue (p<0.0001). A different set of serum samples show a significant increase in circulating AGE in ER+ patients when compared to ER- (p=0.034). In vitro, increased AGE levels can nullify the inhibitory effect of tamoxifen by activating ERK and AKT as well as phosphorylating key serine residues on ERa (shown on western blot and cytotoxic assay). In the proof-of-concept study, cardiac rehab training was shown to lower AGE metabolite levels in breast cancer patients.
Discussion: AGEs not only play a role in the development of cancer, but also the treatment of cancer. Understanding the dietary implications of cancer treatment and the important role AGEs play allows us to take a more personalized approach to cancer treatment. AGE metabolite levels can be used as a biomarker for lifestyle change, giving clinicians a useful tool to track treatment or risk.
Walter KR, Ford ME, Gregoski MJ, et al. Advanced glycation end products are elevated in estrogen receptor-positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention. Breast Cancer Res Treat. 2019;173(3):559-571. doi:10.1007/s10549-018-4992-7
Polymorphisms of the receptor for advanced glycation end products and glyoxalase I and long-term outcome in patients with breast cancer.
Impact Factor: 3.650
Level of Evidence: Level IV
Type of Study: Case-control
Sample Size: 116 unrelated Caucasian women in a large tertiary center in the Department of Oncology of the General University Hospital in Prague (6 patients lost follow-up; long-term data on 110 patients). Exclusion criteria included patients suffering from type 2 diabetes and with serum creatinine greater than 120µmol/L.
Introduction: The purpose of this study was to determine if soluble RAGE (sRAGE) and polymorphisms of RAGE and glyoxalase I could be used as predictors of long-term outcome in breast cancer patients, in addition to tissue expression of RAGE and serum levels of sRAGE, which are already in use.
Methods: Patients were recruited to the study with a mean age of 61.2±11.9 years and had their serum samples collected between October 21, 2003 and March 3, 2005. Their database was closed March 30, 2015. These patients were examined after breast surgery and at the end of chemotherapy. They were divided based on histological grading, expression of estrogen and the C-erb B2/Her2-neu receptors, and clinical stages of the disease, which was based on the tumor-node-metastasis (TNM) classification—stages I-IV. 92 unrelated healthy women also had sRAGE and polymorphisms of RAGE assessed. Fours RAGE gene polymorphisms (-429 T/C—rs1800625, -374 T/A—rs1800624, Gly82Ser—557G/A—rs2070600, and 2184 A/G— rs3134940) and 419 A/C (Ala111Glu—rs 2736654 glyoxalase I polymorphism) were evaluated by PCR and restriction fragment analysis via DNA extracted from peripheral blood. sRAGE was measured with sandwich ELISA.
Statistical analysis: The results were expressed as mean±standard deviations. Kaplan-Meier analysis and univariate and multivariate Cox regression was used to evaluate patient survival. A Cox proportional risk model was used to evaluate risk ratios and confidence intervals. Kaplan-Meier analysis was used for constructing survival curves. A Kruskal-Wallis and Mann-Whitney test was used to compare sRAGE between subgroups using generalized linear model (GLM) analysis with bootstrap extension. All results were statistically significant at p<0.05. A log-rank test determined the post hoc power for Kaplan-Meier survival results.
Results: AG heterozygotes of 2184 A/G RAGE polymorphism had lower mortality than AA and GG homozygotes. GS heterozygotes of G82S RAGE polymorphism had higher mortality than GG homozygotes. As shown by a Cox regression analysis, there was higher mortality in patients with AC genotype compared to AA genotype of 419A/C GLO1 polymorphism. With this same analysis, AG heterozygotes of RAGE 2184 A/G polymorphism showed lower mortality from breast cancer than AA homozygotes. Two further observations were made when patients were stratified based on the clinical stage of breast cancer (0-IV). First, GG genotype of 2184 A/G RAGE polymorphism showed higher risk of mortality from breast cancer compared to AA genotype and second, AG heterozygotes had lower mortality compared to AA homozygotes.
Discussion/Conclusions: A relation between RAGE and glyoxalase polymorphisms and long-term outcome in breast cancer patients was demonstrated, specifically of G82S RAGE and 2184 A/G RAGE polymorphism for mortality due to breast cancer, and glyoxylase 419 A/C polymorphism for overall mortality, indicating they have a role in risk for breast cancer as well as in outcomes of patients with breast cancer. The relationship between sRAGE levels and long-term outcomes for breast cancer patients could not be confirmed. A possible confounding factor regarding the prediction of patient outcome based on sRAGE serum levels demonstrated that while lower sRAGE levels could contribute to disease progression, progression itself could increase sRAGE levels as a compensatory mechanism. The data presented suggested that RAGE activation and impaired AGEs degradation are potentially involved in breast cancer progression. Limitations: Small sample size
Tesarova P, Zima T, Kubena AA, Kalousova M. Polymorphisms of the receptor for advanced glycation end products and glyoxalase I and long-term outcome in patients with breast cancer. Tumour Biol. 2017 Jul;39(7):1010428317702902. doi: 10.1177/1010428317702902. PMID: 28695773.