DNA Damage and Repair Mechanisms, Obesity, and Breast Cancer Disparities

DNA 损伤和修复机制、肥胖和乳腺癌差异

基本信息

批准号：
10306115
负责人：
Chiranjeev Dash
金额：
$ 21.88万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10306115
关键词：
Affect Aging Antioxidants Apoptosis Automobile Driving Base Excision Repairs Biological Assay Bleomycin Body mass index Breast Cancer Patient Breast Cancer Risk Factor Breast Cancer Treatment Breast Cancer survivor Cancer Etiology Cell Proliferation Chronic Complex DNA Damage DNA Repair DNA Repair Pathway Data Diagnosis Double Strand Break Repair Epigenetic Process Equilibrium Excision Free Radicals Gene Expression Generations Genes Genome Stability Genomic Instability Genomics Goals Heart Diseases Hydrogen Peroxide Inflammation Insulin Resistance Leukocytes Linear Regressions Lipids Malignant Neoplasms Measurement Measures Mediator of activation protein Metabolic Nitrogen Nonmetastatic Not Hispanic or Latino Nucleotide Excision Repair Obesity Overweight Oxidation-Reduction Oxidative Stress Oxygen Participant Pathway interactions Physical activity Play Post-Translational Protein Processing Predisposition Premature aging syndrome Prognosis Proteins Race Reducing Agents Regression Analysis Reproducibility Resistance Role Sampling Signal Transduction Single Strand Break Repair Source Survivors Tumor Angiogenesis Tumor Biology Weight Gain Woman Work age related base black women breast cancer survival cancer care cancer cell cancer health disparity cancer recurrence cell motility chemotherapy comorbidity differences in access high risk innovation mRNA Expression malignant breast neoplasm mortality mortality disparity negative affect obese person obesity risk oxidation protein degradation recruit repaired survival disparity tumor progression waist circumference

项目摘要

In this collaborative study, we will investigate obesity-associated DNA damage and repair mechanisms as drivers of mortality disparities between Non-Hispanic Black (NHB) and White (NHW) breast cancer survivors. Breast cancer is the most common cancer; and a major source of Black-White cancer mortality disparities among women in the US. Mortality from breast cancer is 27% higher in NHB than NHW women. In addition to differences in access and quality of cancer care, tumor biology and genomic factors play an important role in these disparities. However, basic mechanisms driving these complex survival disparities are still unclear. Genome stability, DNA damage and repair are hallmarks of cancer and are established factors associated with prognosis after breast cancer. However, differences in DNA damage and repair capacity as a major mechanism for breast cancer survival disparities between NHB and NHW women has not been studied. Our preliminary data from our work and others suggest DNA damage and DNA repair mechanisms might differ by race in breast cancer. Obesity is an independent risk factor for breast cancer recurrence and mortality. We, and others, have shown that a majority of women gain weight during breast cancer treatment, with those undergoing chemotherapy and those overweight at diagnosis, being at the highest risk for weight gain. Black women with breast cancer are more likely to receive chemotherapy, less likely to engage in physical activity, and are more likely to be overweight/obese at diagnosis, thus putting them at higher risk of obesity-associated DNA damage. Increased oxidative stress, through generation of damaging free radicals, can cause obesity- related genomic instability and reduced DNA repair capacity. This results in excessive DNA damage accumulation leading to early aging and cancer recurrence and mortality. In addition, obesity-related early aging might also be responsible for increased metabolic abnormalities and age-related comorbidities (e.g., heart disease) among survivors leading to mortality disparities in breast cancer. Therefore, we hypothesize that increased adiposity, through oxidative stress is primarily responsible for DNA damage differences seen between NHB and NHW breast cancer patients. Specific DNA repair pathways, such as base excision/single- strand break repair (BER/SSBR), nucleotide excision repair (NER), and double-strand break repair (DSBR) pathways are negatively affected in overweight/obese people. Obesity-induced DNA damaging agents reduce DNA repair capacity by affecting gene expression, and protein inactivation/degradation via direct protein modifications. We also hypothesize that increased adiposity is associated with reduced mRNA expression, protein degradation/inactivation, and overall reduced functional repair capacity in key selected DNA repair pathways. The goal of this study is to (1) determine differences in basal DNA damage and DNA damage susceptibility and repair mechanisms between NHB and NHW survivors; and (2) investigate the role of obesity, oxidative stress and obesity-associated select repair pathways in these differences.

在这项合作研究中，我们将研究与肥胖相关的 DNA 损伤和修复机制：非西班牙裔黑人 (NHB) 和白人 (NHW) 乳腺癌幸存者之间死亡率差异的驱动因素。乳腺癌是最常见的癌症；也是黑人与白人癌症死亡率差异的主要根源在美国女性中。 NHB 女性的乳腺癌死亡率比 NHW 女性高 27%。此外癌症护理的获取和质量、肿瘤生物学和基因组因素的差异在这些差异。然而，导致这些复杂的生存差异的基本机制仍不清楚。基因组稳定性、DNA 损伤和修复是癌症的标志，也是与癌症相关的既定因素乳腺癌后的预后。然而，DNA损伤和修复能力的差异是主要因素 NHB 和 NHW 女性之间乳腺癌生存差异的机制尚未研究。我们的我们和其他人的工作的初步数据表明 DNA 损伤和 DNA 修复机制可能因以下原因而有所不同：乳腺癌的种族。肥胖是乳腺癌复发和死亡的独立危险因素。我们，等人的研究表明，大多数女性在乳腺癌治疗期间体重增加，其中正在接受化疗的人和诊断时超重的人，体重增加的风险最高。黑色的患有乳腺癌的女性更有可能接受化疗，不太可能进行体力活动，并且在诊断时更有可能超重/肥胖，从而使他们面临与肥胖相关的更高风险 DNA损伤。通过产生破坏性自由基，氧化应激增加可导致肥胖—— 相关的基因组不稳定和 DNA 修复能力降低。这会导致过度的 DNA 损伤积累导致早衰和癌症复发和死亡。此外，与肥胖相关的早期衰老也可能导致代谢异常和与年龄相关的合并症增加（例如，心脏病）在幸存者中导致乳腺癌死亡率差异。因此，我们假设氧化应激导致的肥胖增加是造成 DNA 损伤差异的主要原因 NHB 和 NHW 乳腺癌患者之间的关系。特定的 DNA 修复途径，例如碱基切除/单修复链断裂修复 (BER/SSBR)、核苷酸切除修复 (NER) 和双链断裂修复 (DSBR) 超重/肥胖者的途径受到负面影响。肥胖引起的 DNA 损伤剂减少通过影响基因表达实现 DNA 修复能力，通过直接蛋白质实现蛋白质失活/降解修改。我们还假设肥胖增加与 mRNA 表达减少有关，蛋白质降解/失活，以及关键选定 DNA 修复中功能修复能力的总体降低途径。本研究的目标是 (1) 确定基础 DNA 损伤和 DNA 损伤的差异 NHB 和 NHW 幸存者之间的易感性和修复机制； (2) 研究肥胖的作用，氧化应激和肥胖相关的选择修复途径存在这些差异。