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Grant Details

Grant Number: 5R01CA220693-05 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: 2021


Abstract

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.



Publications

The perils of generalization: Rethinking breast cancer screening guidelines for young women of color.
Authors: Seewaldt V.L. , Bernstein L. .
Source: Cancer, 2021-08-24; , .
EPub date: 2021-08-24.
PMID: 34427914
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Breast-Specific Molecular Clocks Comprised of ELF5 Expression and Promoter Methylation Identify Individuals Susceptible to Cancer Initiation.
Authors: Miyano M. , Sayaman R.W. , Shalabi S.F. , Senapati P. , Lopez J.C. , Angarola B.L. , Hinz S. , Zirbes A. , Anczukow O. , Yee L.D. , et al. .
Source: Cancer prevention research (Philadelphia, Pa.), 2021 Aug; 14(8), p. 779-794.
EPub date: 2021-06-17.
PMID: 34140348
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Interdisciplinary data science to advance environmental health research and improve birth outcomes.
Authors: Stingone J.A. , Triantafillou S. , Larsen A. , Kitt J.P. , Shaw G.M. , Marsillach J. .
Source: Environmental research, 2021 06; 197, p. 111019.
EPub date: 2021-03-15.
PMID: 33737076
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Time for action: The Patient Protection and Affordable Care Act Medicaid expansion significantly improves breast cancer care for women in Louisiana.
Authors: Seewaldt V.L. .
Source: Cancer, 2021-03-01; 127(5), p. 672-675.
EPub date: 2020-11-03.
PMID: 33141930
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Spatiotemporal strategies to identify aggressive biology in precancerous breast biopsies.
Authors: Frankhauser D.E. , Jovanovic-Talisman T. , Lai L. , Yee L.D. , Wang L.V. , Mahabal A. , Geradts J. , Rockne R.C. , Tomsic J. , Jones V. , et al. .
Source: Wiley interdisciplinary reviews. Systems biology and medicine, 2020-10-01; , p. e1506.
EPub date: 2020-10-01.
PMID: 33001587
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Using Latent Class Modeling to Jointly Characterize Economic Stress and Multipollutant Exposure.
Authors: Larsen A. , Kolpacoff V. , McCormack K. , Seewaldt V. , Hyslop T. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020 10; 29(10), p. 1940-1948.
EPub date: 2020-08-20.
PMID: 32856601
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Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth.
Authors: Ishak Gabra M.B. , Yang Y. , Li H. , Senapati P. , Hanse E.A. , Lowman X.H. , Tran T.Q. , Zhang L. , Doan L.T. , Xu X. , et al. .
Source: Nature communications, 2020-07-03; 11(1), p. 3326.
EPub date: 2020-07-03.
PMID: 32620791
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Breast Self-Examination - the case for a second look.
Authors: Dietze E. , Jones V. , Seewaldt V. .
Source: Current breast cancer reports, 2020 Jun; 12(2), p. 118-124.
EPub date: 2020-02-26.
PMID: 34149989
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A Non-canonical Function of BMAL1 Metabolically Limits Obesity-Promoted Triple-Negative Breast Cancer.
Authors: Ramos C.A. , Ouyang C. , Qi Y. , Chung Y. , Cheng C.T. , LaBarge M.A. , Seewaldt V.L. , Ann D.K. .
Source: iScience, 2020-02-21; 23(2), p. 100839.
EPub date: 2020-01-14.
PMID: 32058954
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Environmental Exposures during Puberty: Window of Breast Cancer Risk and Epigenetic Damage.
Authors: Natarajan R. , Aljaber D. , Au D. , Thai C. , Sanchez A. , Nunez A. , Resto C. , Chavez T. , Jankowska M.M. , Benmarhnia T. , et al. .
Source: International journal of environmental research and public health, 2020-01-13; 17(2), .
EPub date: 2020-01-13.
PMID: 31941024
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The KRAS-variant and its impact on normal breast epithelial cell biology.
Authors: Jung S.Y. , Malhotra P. , Nguyen K.C. , Salzman D. , Qi Y. , Pak E.H. , King J. , Vlashi E. , Ann D. , Weidhaas J.B. .
Source: Cell death and differentiation, 2019 12; 26(12), p. 2568-2576.
EPub date: 2019-04-01.
PMID: 30932013
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Mammographic density: intersection of advocacy, science, and clinical practice.
Authors: Tossas-Milligan K. , Shalabi S. , Jones V. , Keely P.J. , Conklin M.W. , Eliceiri K.W. , Winn R. , Sistrunk C. , Geradts J. , Miranda-Carboni G. , et al. .
Source: Current breast cancer reports, 2019 09; 11(3), p. 100-110.
EPub date: 2019-07-24.
PMID: 33312342
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Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer.
Authors: Senapati P. , Kato H. , Lee M. , Leung A. , Thai C. , Sanchez A. , Gallagher E.J. , LeRoith D. , Seewaldt V.L. , Ann D.K. , et al. .
Source: Epigenetics & chromatin, 2019-07-17; 12(1), p. 44.
EPub date: 2019-07-17.
PMID: 31315653
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IL15 Enhances CAR-T Cell Antitumor Activity by Reducing mTORC1 Activity and Preserving Their Stem Cell Memory Phenotype.
Authors: Alizadeh D. , Wong R.A. , Yang X. , Wang D. , Pecoraro J.R. , Kuo C.F. , Aguilar B. , Qi Y. , Ann D.K. , Starr R. , et al. .
Source: Cancer immunology research, 2019 05; 7(5), p. 759-772.
EPub date: 2019-03-19.
PMID: 30890531
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A Novel Angiotensin II-Induced Long Noncoding RNA Giver Regulates Oxidative Stress, Inflammation, and Proliferation in Vascular Smooth Muscle Cells.
Authors: Das S. , Zhang E. , Senapati P. , Amaram V. , Reddy M.A. , Stapleton K. , Leung A. , Lanting L. , Wang M. , Chen Z. , et al. .
Source: Circulation research, 2018-12-07; 123(12), p. 1298-1312.
PMID: 30566058
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LTRs activated by Epstein-Barr virus-induced transformation of B cells alter the transcriptome.
Authors: Leung A. , Trac C. , Kato H. , Costello K.R. , Chen Z. , Natarajan R. , Schones D.E. .
Source: Genome research, 2018 12; 28(12), p. 1791-1798.
EPub date: 2018-10-31.
PMID: 30381291
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Diabetes Mellitus-Induced Long Noncoding RNA Dnm3os Regulates Macrophage Functions and Inflammation via Nuclear Mechanisms.
Authors: Das S. , Reddy M.A. , Senapati P. , Stapleton K. , Lanting L. , Wang M. , Amaram V. , Ganguly R. , Zhang L. , Devaraj S. , et al. .
Source: Arteriosclerosis, thrombosis, and vascular biology, 2018 08; 38(8), p. 1806-1820.
PMID: 29930005
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When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance.
Authors: Kuo C.Y. , Ann D.K. .
Source: Cancer communications (London, England), 2018-07-11; 38(1), p. 47.
EPub date: 2018-07-11.
PMID: 29996946
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Chromatin modifications in metabolic disease: Potential mediators of long-term disease risk.
Authors: Costello K.R. , Schones D.E. .
Source: Wiley interdisciplinary reviews. Systems biology and medicine, 2018 07; 10(4), p. e1416.
EPub date: 2018-01-25.
PMID: 29369528
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Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction.
Authors: Cheng C.T. , Qi Y. , Wang Y.C. , Chi K.K. , Chung Y. , Ouyang C. , Chen Y.R. , Oh M.E. , Sheng X. , Tang Y. , et al. .
Source: Communications biology, 2018; 1, p. 178.
EPub date: 2018-10-26.
PMID: 30393775
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Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells.
Authors: Das S. , Senapati P. , Chen Z. , Reddy M.A. , Ganguly R. , Lanting L. , Mandi V. , Bansal A. , Leung A. , Zhang S. , et al. .
Source: Nature communications, 2017-11-13; 8(1), p. 1467.
EPub date: 2017-11-13.
PMID: 29133788
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