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，如 非西班牙裔黑人(NHB)和白人(NHW)乳腺癌幸存者死亡率差异的驱动因素。 乳腺癌是最常见的癌症；也是黑白癌症死亡率差异的主要来源 在美国的女性中。NHB的乳腺癌死亡率比NHW妇女高27%。除了……之外 癌症护理的机会和质量、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距的基本机制仍然不清楚。 基因组稳定性、DNA损伤和修复是癌症的标志，也是与 乳腺癌的预后。然而，DNA损伤和修复能力的差异是主要的 NHB和NHW妇女之间乳腺癌存活率差异的机制尚未被研究。我们的 我们和其他人的初步数据表明，DNA损伤和DNA修复机制可能不同于 乳腺癌赛跑。肥胖是乳腺癌复发和死亡的独立危险因素。我们, 和其他的研究表明，大多数女性在乳腺癌治疗过程中体重增加， 接受化疗和确诊时超重的人，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， 而且在确诊时更有可能超重/肥胖，因此他们患肥胖症的风险更高 DNA损伤。氧化应激增加，通过产生破坏性的自由基，可能会导致肥胖- 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。 积聚会导致早衰、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共病增加(例如， 存活者中的心脏病)导致乳腺癌死亡率差异。因此，我们假设 肥胖增加，通过氧化应激是DNA损伤的主要原因 NHB和NHW乳腺癌患者之间的差异。特定的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) 超重/肥胖者的神经通路会受到负面影响。肥胖导致的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的蛋白质失活/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修复中整体功能修复能力的降低 小路。这项研究的目的是(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；以及(2)调查肥胖的作用， 氧化应激和肥胖相关的修复途径在这些差异中选择。

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.