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

项目总结 非裔美国人(AA)女性受三重阴性乳腺癌(TNBC)的影响不成比例，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的再障患者有更高的 与欧美(EA)同行相比，他们死于这种疾病的风险独立于他们 社会人口学和临床因素。值得注意的是，这种TNBC差异在接受 化疗。然而，驱动肿瘤对化疗和化疗的不同反应的分子机制 因此AA与EA TNBCs之间的预后差异仍不清楚。大多数化疗药物都会 它们的细胞毒作用是通过诱导致命的DNA双链断裂(DSB)来实现的，DSB可以通过 两种主要机制：无错误的同源重组(HR)和容易出错的非同源末端- 加入(NHEJ)。已知基因毒性治疗下肿瘤细胞的基因组稳定性和存活率取决于 在人力资源部。我们的初步研究表明，AA TNBCs倾向于高表达HR相关蛋白和 与电针TNBCs相比，NHEJ相关蛋白表达降低。AAA ATPase VCP已经被 建议影响DSB修复途径的选择，有利于HR而不是NHEJ。我们最近 报道VCP的Ser784磷酸化是DNA损伤修复和肿瘤内pSer784-VCP所必需的 水平预示着TNBC患者，特别是那些接受化疗的患者存活率较低。我们的试点数据也 结果表明，AA组总VCP蛋白水平和DNA损伤诱导的pSer784-VCP水平均高于EA组 TNBC样本。基于这些数据，我们假设AA TNBC相对于EA TNBC本质上是 HR比NHEJ更有能力修复化疗所致的DSB 包括pSer784-VCP在内的DSB修复因子的表达水平和功能是其更糟糕的基础 临床结果。我们提出了三个具体目标。首先，我们将确认蛋白质表达的种族差异 检测两大TNBC患者肿瘤组织中HR和NHEJ因子的表达 对生存差距的贡献。其次，我们将通过实验比较HR和NHEJ的效率 AA和EA TNBC细胞系和患者来源的小鼠异种移植(PDX)模型，并与种族相关 DSB修复途径选择和基因毒性化疗效果的差异。第三，我们将研究 PSer784-VCP对再障TNBC DSB修复途径选择和基因毒性化疗效应的调节作用 模特们。拟议中的研究将极大地提高我们对潜在的分子机制的理解。 TNBC治疗反应和结果的种族差异。这一结果还将有助于造成新的差距 通过建立pSer784-VCP作为新的预测生物标志物和增敏靶点的干预策略 再障TNBCs的基因毒性化疗治疗。 。

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. .