Pre-diabetes is associated with increased breast cancer risk. Recent studies have recognized a role for intermittent fasting, in the form of early time restricted feeding (TRF), in avoiding circadian de-synchrony to improve insulin resistance. TRF is an eating pattern that prolongs the overnight fasting duration by coordinating caloric intake with light-dark circadian rhythm. Prolonged nighttime fasting duration may be associated with reduced breast cancer and recurrence risk. The underlying mechanistic aspects of prolonged overnight fasting duration and relationship to breast cancer risk is not yet known. Advanced glycation end products (AGEs) are reactive metabolites that accumulate in tissues as we grow older. We now consume copious amounts of AGEs as part of the modern diet. The pathogenic effects of AGEs contribute to insulin resistance, diabetes and cancer through the aberrant activation of stress response pathways. A high impact finding of our animal studies is that dietary-AGE induced increases in breast tumor growth are restricted by TRF. Dietary-AGE mediated increases in breast tumor growth were dependent upon the stromal expression of the transmembrane receptor for AGE (RAGE). Soluble RAGE (sRAGE) is a broad term used to define various truncated forms of full length RAGE that are found in the circulation. It encompasses a group of tumor suppressive variants of the oncogenic full RAGE, thought to sequester AGE in the circulation by acting as a decoy receptor. Accompanying the TRF mediated decreases in dietary-AGE induced tumor growth was a significant increase in sRAGE. We hypothesize that TRF induced increases in sRAGE may represent a cancer risk modification by reducing AGE-RAGE toxicity in patients with pre-diabetes. The objective of this study is to assess the impact of TRF on AGE-RAGE toxicity in women at higher risk of breast cancer, and explore the mechanistic implications of TRF induced sRAGE in dietary-AGE mouse tumor models. We propose two specific aims; To conduct a pilot Randomized Controlled Trial (RCT) designed to measure the effect of TRF on AGE-RAGE toxicity in postmenopausal women with pre-diabetes (SA1) and to examine the mechanism of sRAGE upregulation in response to TRF in vivo (SA2). It is essential to identify disease risk factors in order to modify therapies aimed at decreasing breast cancer risk in vulnerable populations. sRAGE has been identified as clinically important in diabetes and breast cancer. As the epidemic of diabetes continues to expand, increasing the number of women at high risk of breast cancer, identifying the mechanism and type of sRAGE increased in response to TRF will provide a platform for larger intervention studies. Such studies would be aimed at further defining the potential of targeting environmental AGE as a cancer prevention strategy through fasting.

Project Narrative The mechanistic aspects of prolonged overnight fasting duration and relationship to breast cancer risk is needed. We have identified a mechanistic link between lifestyle-associated AGEs, time restricted feeding and sRAGE that in the long term could lead to interventions to improve outcomes for women at higher risk of developing breast cancer. A greater understanding of the molecular mechanisms that increase breast cancer risk in response to a high AGE diet will allow the development of novel strategies to prevent or reverse this process in high risk individuals, like women with pre-diabetes.