Thursday, November 21, 2024
11/21/2024
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.
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