Grant Number:	5R01CA220693-04 Interpret this number
Primary Investigator:	Seewaldt, Victoria
Organization:	Beckman Research Institute/City Of Hope
Project Title:	Epigenetic Damage in Women Living in LA Food-Desert Zip Codes
Fiscal Year:	2020

In the United States, people living in low-income neighborhoods frequently do not have access to affordable healthy food (“food-deserts”). People living in food-deserts must rely on convenience stores and fast-food chains that offer few, if any, healthy food choices, such as fruits and vegetables. The failure of supermarket chains to locate stores that offer fresh fruits and vegetables in inner-city communities—a form of food redlining—has had a profound impact on the nutrition, health, and well-being of many of our citizens, particularly young Men- and Women-of-Color. Young Women-of-Color (African-American and Latina/Hispanic- American) are more likely to live in food-deserts than their European-American counterparts. The lack of healthy food choices puts young Women-of-Color at increased risk for type-2 diabetes, obesity, and triple- negative breast cancer (TNBC). Although obesity, diabetes, and TNBC are distinct diseases, they do not occur in isolation. Obesity is a significant risk factor for TNBC and insulin promotes many signaling pathways that define the aggressive biology of TNBC. At our City of Hope Clinics in Los Angeles, 37% of young Women-of- Color who are at high risk for TNBC also have pre-diabetes (insulin resistance). Here we aim to test in young Women-of-Color living in food-desert zip codes in Los Angeles, whether insulin-resistance promotes epigenetic damage and increases TNBC-risk. Insulin resistance occurs when cells stop responding to insulin. Every time a woman with insulin-resistance eats, serum insulin spikes to 5-10 times normal (hyperinsulinemia). Insulin drives mitochondrial respiration and increases production of bioactive metabolites such as acetyl-coenzyme A (acetyl-CoA). Hyperinsulinemia overdrives the mitochondrial electron transport chain and drives excessive production of bioactive metabolites, such as acetyl-CoA. Recent evidence shows that overproduction of acetyl- CoA hyper-acetylates histone proteins and promotes inappropriate chromatin opening and long-term epigenetic damage. We hypothesize that metformin 1) will normalize circulating insulin levels and reduce acetyl-CoA production but, 2) will not reverse epigenetic damage. Aim 1 will characterize the environment and women living in City of Hope catchment area food-desert zip codes. Aim 2 will test whether insulin-driven mitochondrial dysfunction increase chromatin accessibility and genomic instability. Aim 3 will investigate whether insulin-driven epigenetic damage associated with insulin-resistance will be reversed by metformin. Significance: If our hypothesis is correct — that we can only prevent new epigenetic damage, but cannot reverse epigenetic damage once it occurs — it is important to institute early aggressive treatment of pre- diabetes in women at high-risk for TNBC and work aggressively to enact public policy to end food-deserts.




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