Understanding the role of DNA damage repair in racial disparities of triple-negative breast cancer outcomes

了解 DNA 损伤修复在三阴性乳腺癌结果种族差异中的作用

• 批准号: 10561640
• 负责人: Ying Liu
• 金额: $ 45.97万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-03 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561640
• 关键词: ATP phosphohydrolase; Adjuvant Chemotherapy; Affect; African American; Aggressive Clinical Course; American; Automobile Driving; Biological; Biological Assay; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; Cancer cell line; Cell Line; Cell Survival; Cells; Chemoresistance; Chemosensitization; Chromatin; Clinical; Coupled; DNA; DNA Crosslinking Agent; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Data; Data Set; Disease; Disparity; Double Strand Break Repair; Encyclopedias; European; Excision; FANCD2 protein; Fluorescence; G22P1 gene; GMNN gene; Genome Stability; Immunohistochemistry; In Vitro; Incidence; Intervention; Link; Malignant neoplasm of ovary; Measures; Molecular; Mus; Mutagens; Neoadjuvant Therapy; Nonhomologous DNA End Joining; Not Hispanic or Latino; Nuclear; Outcome; Pathway interactions; Patients; Pattern; Phosphorylation; Pilot Projects; Poly(ADP-ribose) Polymerase Inhibitor; Prognosis; Protein Dynamics; Protein Inhibition; Proteins; Proteomics; Race; Reporter; Reporting; Role; Sample Size; Sampling; Site; Testing; The Cancer Genome Atlas; Tissues; Treatment Efficacy; Treatment outcome; Tumor Tissue; Woman; Xenograft Model; brca gene; cancer cell; cancer health disparity; chemotherapy; chromatin protein; cohort; cytotoxic; differential expression; genotoxicity; high risk; homologous recombination; hormone receptor-positive; improved; improved outcome; in vivo Model; inhibitor; knock-down; malignant breast neoplasm; mortality; mortality risk; mutant; neoplastic cell; novel; outcome disparities; p53-binding protein 1; personalized medicine; predictive marker; prognostic; protein expression; racial difference; racial disparity; relapse risk; repaired; response; sociodemographics; survival disparity; survival outcome; therapeutic target; treatment response; triple-negative invasive breast carcinoma; tumor; valosin-containing protein

PROJECT SUMMARY African American (AA) women are disproportionately affected by triple negative breast cancer (TNBC), a highly heterogeneous and aggressive subtype of breast cancer. We found that AA patients with TNBC have a higher risk of death from the disease than their European American (EA) counterparts, which is independent of their sociodemographic and clinical factors. Notably, this TNBC disparity is more obvious in patients receiving chemotherapy. However, the molecular mechanisms driving differential tumor response to chemotherapy and the consequent prognostic disparities in AA vs. EA TNBCs remains unknown. Most chemotherapy agents exert their cytotoxic effects through the induction of deadly DNA double-strand breaks (DSBs) that are repaired by two major mechanisms: error-free homologous recombination (HR) and error-prone non-homologous end- joining (NHEJ). Genomic stability and survival of tumor cells upon genotoxic treatments are known to depend on HR. Our pilot study showed that AA TNBCs tend to have higher expression of HR-related proteins and lower expression of NHEJ-related proteins compared with EA TNBCs. The AAA+ ATPase VCP has been suggested to influence the choice of DSB repair pathways in favor of HR as opposed to NHEJ. We recently reported that Ser784 phosphorylation of VCP is required for DNA damage repair and intra-tumor pSer784-VCP levels predict poor survival in TNBC patients, particularly those receiving chemotherapy. Our pilot data also showed that both total VCP protein and DNA damage-induced pSer784-VCP levels are higher in AA vs. EA TNBC samples. Based on these data, we hypothesize that AA TNBCs, relative to EA TNBCs, are intrinsically more capable of repairing chemotherapy-induced DSBs by HR as opposed to NHEJ due to differential expression levels and functionality of DSB repair factors including pSer784-VCP, which underlies their worse clinical outcomes. We propose three specific aims. First, we will confirm racial differences in protein expression of HR and NHEJ factors in tumor tissues obtained from two large cohorts of TNBC patients and examine their contribution to survival disparities. Second, we will experimentally compare HR and NHEJ efficiencies between AA and EA TNBC cell line and patient-derived mouse xenograft (PDX) models, and correlate the racial differences in DSB repair pathway choice and genotoxic chemotherapy effects. Third, we will examine the ability of pSer784-VCP to regulate DSB repair pathway choice and genotoxic chemotherapy effects in AA TNBC models. The proposed study will greatly improve our understanding of the molecular mechanisms underlying racial disparities in TNBC treatment response and outcomes. The results will also help create new disparity intervention strategies by establishing pSer784-VCP as a novel predictive biomarker and sensitizing target for genotoxic chemotherapy treatments in AA TNBCs. .

项目概要 非裔美国 (AA) 女性不成比例地受到三阴性乳腺癌 (TNBC) 的影响，这是一种高度 乳腺癌的异质性和侵袭性亚型。我们发现患有 TNBC 的 AA 患者具有更高的 死于该疾病的风险高于欧洲美国人 (EA) 同行，这与他们的情况无关 社会人口统计学和临床​​因素。值得注意的是，这种 TNBC 差异在接受治疗的患者中更为明显 化疗。然而，驱动肿瘤对化疗和治疗的不同反应的分子机制 AA 与 EA TNBC 的后续预后差异仍然未知。大多数化疗药物发挥作用 它们通过诱导致命的 DNA 双链断裂 (DSB) 来发挥细胞毒性作用，而双链断裂可通过以下方法修复： 两个主要机制：无错同源重组（HR）和易错非同源重组 加入（NHEJ）。已知基因毒性治疗后肿瘤细胞的基因组稳定性和存活率取决于 关于人力资源。我们的初步研究表明，AA TNBC 往往具有较高的 HR 相关蛋白表达，并且 与 EA TNBC 相比，NHEJ 相关蛋白的表达较低。 AAA+ ATPase VCP 已 建议影响 DSB 修复途径的选择，有利于 HR 而不是 NHEJ。我们最近 据报道，VCP Ser784 磷酸化是 DNA 损伤修复和肿瘤内 pSer784-VCP 所必需的 水平预测 TNBC 患者的生存率较差，尤其是接受化疗的患者。我们的试点数据还 结果表明，AA 中的总 VCP 蛋白和 DNA 损伤诱导的 pSer784-VCP 水平高于 EA TNBC 样本。基于这些数据，我们假设 AA TNBC 相对于 EA TNBC 本质上是 由于差异性，HR 比 NHEJ 更有能力修复化疗引起的 DSB DSB 修复因子（包括 pSer784-VCP）的表达水平和功能，这是其更差的基础 临床结果。我们提出三个具体目标。首先，我们将确认蛋白质表达的种族差异 研究人员对从两大组 TNBC 患者获得的肿瘤组织中的 HR 和 NHEJ 因子进行了分析，并检查了它们的 生存差异的贡献。其次，我们将通过实验比较 HR 和 NHEJ 效率 AA 和 EA TNBC 细胞系和患者来源的小鼠异种移植 (PDX) 模型，并将种族 DSB修复途径选择和基因毒性化疗效果的差异。第三，我们将检查 pSer784-VCP 调节 AA TNBC 中 DSB 修复途径选择和基因毒性化疗效应的能力 模型。拟议的研究将极大地提高我们对潜在分子机制的理解 TNBC 治疗反应和结果的种族差异。结果也将有助于创造新的差距 通过建立 pSer784-VCP 作为新型预测生物标志物和敏化靶标来制定干预策略 AA TNBC 中的基因毒性化疗。 。