DUSTIN E SCHONES - US grants

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.

Project Summary/Abstract A dramatic increase in the prevalence of obesity and related complications over the last few decades has led to a worldwide epidemic. In the U.S. alone, approximately one in three adults over the age of 20 are obese and are at risk for cardiovascular disease, fatty liver, type 2 diabetes and several types of cancer. Our recent work has demonstrated that diet-induced obesity (DIO), but means of a ?western? high fat and high sucrose diet lead to persistent epigenetic modifications in the liver, thereby mediating pervasive changes in transcriptional regulatory programs. Notably, we identified a strong genetic component to these environmentally induced epigenetic modifications with the sites of obesity associated epigenetic modifications being largely specific to individual strains of mice. Strikingly, a large proportion of the epigenetic variation we observed across strains occurred at transposable elements (TEs). These genomic elements constitute approximately half of the human and mouse genomes and have contributed to the evolution of genomes and genomic diversity. While certain classes of TEs are known to be active in early developmental cells, they are generally transcriptionally silenced in later stages of development through mechanisms such as DNA methylation. There is increasing evidence, however, that TEs can be activated somatically and that this dysregulation can contribute to altered gene regulatory programs and disease progression. Our recent work indicates that TEs can be dysregulated in the liver under obesogenic conditions and alter the regulation of genes important for metabolism. Despite the increasing evidence of the importance of TE dysregulation in altering gene regulation and disease progression, the mechanisms responsible for this dysregulation remain poorly understood. According to our hypothesis, obesogenic conditions promote the epigenetic dysregulation of TEs through alterations in DNA methylation profiles and that this can be prevented or reversed therapeutically. Our aims are to: 1) characterize the obesogenic conditions involved in TE dysregulation, 2) determine the role of DNA methylation in mediating obesity associated TE dysregulation and 3) determine if TE dysregulation can be prevented or reversed through dietary supplementation. The results generated from this proposed work will explore a novel molecular mechanism that is associated with the progression of obesity and related complications. These results will furthermore provide a greater understanding of how dysregulation of TEs contribute to other diseases.

Abstract: Currently there are no biomarkers to separate good from poor prognosis luminal B breast cancers. Poor prognosis luminal B breast cancers are only identified after a woman fails to respond to neo-adjuvant therapy and options for cure are limited. While recent efforts have focused on developing targeted agents for triple- negative breast cancer, luminal B breast cancer has been understudied, particularly in Latina/Hispanic women. Here, we aim to investigate the biology of aggressive luminal B breast cancers in Latina/Hispanic women with the overall goal of improving early detection and survival. Overexpression of the oncogenic transcription factor c-MYC (MYC) promotes malignant transformation and predicts poor prognosis in women with luminal B breast cancers. Recent studies show that, relative to Northern European Whites, Black women with luminal B breast cancers have a high-frequency of MYC-overexpression[5]. Preliminary studies provide evidence that MYC is also frequently overexpressed in Latinas. UC Riverside (UCR) P20 PI Dr. Ernest Martinez studies the mechanistic role of MYC-acetylation in promoting glycolysis and cellular transformation. City of Hope (CoH) investigator, Dustin Schones studies the role of glycolysis in driving abnormal chromatin acetylation and aberrant transcription. In this pilot, we aim to leverage these discoveries to target MYC-acetylation for drug development. In this Early Drug Pipeline Pilot study, we aim to test the hypothesis that MYC-driven mitochondrial Acetyl-CoA overproduction in luminal B breast cancer 1) promotes abnormal chromatin opening and enhances the oncogenic functions of MYC and 2) predicts poor survival. Findings will be translated to test whether MYC-acetylation is a promising target for early detection and/or treatment of luminal B breast cancer in Latinas. Aim 1 will test whether chromatin acetylation and/or acetylation of the MYC oncogenic transcription factor predicts poor prognosis in Southern California Latinas with luminal B breast cancer. Aim 2 will target the acetylation/metabolic functions of MYC in high-throughput screening and mouse PDX models derived from MYC+ luminal B breast cancers from Los Angeles Latina women.