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

在这项合作研究中，我们将研究肥胖相关的DNA损伤和修复机制， 非西班牙裔黑人（NHB）和白色（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，也是黑人和白人癌症死亡率差异的主要来源。 在美国女性中。NHB的乳腺癌死亡率比NHW妇女高27%。除了 癌症治疗的可及性和质量、肿瘤生物学和基因组因素的差异在 这些差异。然而，驱动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，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作为一个主要因素， NHB和NHW妇女之间乳腺癌生存差异的机制尚未研究。我们 我们的工作和其他人的初步数据表明，DNA损伤和DNA修复机制可能因 乳腺癌中的种族肥胖是乳腺癌复发和死亡的独立危险因素。我们， 和其他研究表明，大多数女性在乳腺癌治疗期间体重增加， 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 患有乳腺癌的女性更有可能接受化疗，不太可能从事体育活动， 并且在诊断时更有可能超重/肥胖，从而使他们处于肥胖相关的更高风险中。 DNA损伤。增加氧化应激，通过产生有害的自由基，可以导致肥胖- 相关的基因组不稳定性和DNA修复能力降低。这会导致过度的DNA损伤 积累导致早期衰老和癌症复发和死亡。此外，肥胖相关的早期 衰老也可能是代谢异常和年龄相关的合并症增加的原因（例如， 心脏病）导致乳腺癌死亡率的差异。因此，我们假设， 增加肥胖，通过氧化应激是主要负责DNA损伤的差异， NHB和NHW乳腺癌患者之间的差异。特异性DNA修复途径，如碱基切除/单- 链断裂修复（BER/SSBR）、核苷酸切除修复（NER）和双链断裂修复（DSBR） 途径在超重/肥胖人群中受到负面影响。肥胖诱导的DNA损伤剂减少 通过影响基因表达的DNA修复能力，以及通过直接蛋白质失活/降解的蛋白质 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，以及关键选择DNA修复中功能性修复能力的总体降低 途径。本研究的目的是（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;和（2）研究肥胖的作用， 氧化应激和肥胖相关的选择修复途径在这些差异。

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.