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

项目摘要 非洲裔美国人（AA）妇女不成比例地受到三阴性乳腺癌（TNBC）的影响，这是一个高度 异质性和侵袭性亚型乳腺癌。我们发现，患有TNBC的AA患者具有更高的 死亡的风险比他们的欧洲美国（EA）同行，这是独立的，他们的疾病 社会人口学和临床因素。值得注意的是，这种TNBC差异在接受TNBC治疗的患者中更明显。 化疗然而，驱动肿瘤对化疗和化疗药物的不同反应的分子机制， 因此AA与EA TNBC的预后差异仍然未知。大多数化疗药物 它们通过诱导致命的DNA双链断裂（DSB）产生细胞毒性作用， 两种主要机制：无错误同源重组（HR）和易错非同源末端- 加入（NHEJ）。已知基因组稳定性和肿瘤细胞在基因毒性治疗后的存活取决于 我们的初步研究表明，AA TNBC倾向于具有较高的HR相关蛋白表达， 与EA TNBC相比，NHEJ相关蛋白的表达较低。AAA+ ATP酶VCP已被 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Ser 784磷酸化是DNA损伤修复和肿瘤内pSer 784-VCP所必需的 水平预测TNBC患者的生存率较差，特别是那些接受化疗的患者。我们的试点数据还 表明AA中总VCP蛋白和DNA损伤诱导的pSer 784-VCP水平均高于EA TNBC样品。基于这些数据，我们假设AA TNBC相对于EA TNBC本质上是 与NHEJ相比，HR更能修复化疗诱导的DSB， 包括pSer 784-VCP在内的DSB修复因子的表达水平和功能，这是它们更差的基础。 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 HR和NHEJ因子在从两个大的TNBC患者组群获得的肿瘤组织中的表达，并检查其 造成生存差距。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物（PDX）模型，并将种族相关性进行分析。 DSB修复途径选择和遗传毒性化疗效果的差异。第三，我们将研究 pSer 784-VCP调节AA TNBC中DSB修复途径选择和遗传毒性化疗效应的能力 模型这项研究将大大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。结果也将有助于创造新的差距 通过建立pSer 784-VCP作为新的预测生物标志物和敏感靶点的干预策略， AA TNBC中的遗传毒性化疗治疗。 .

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. .