HSET as a racial disparity biomarker for TNBC patients

HSET 作为 TNBC 患者的种族差异生物标志物

• 批准号: 9898334
• 负责人: Ritu Aneja
• 金额: $ 76.35万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-21 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898334
• 关键词: Accounting; Address; Adjuvant; African; African American; American; Automobile Driving; Binding; Biological; Biological Markers; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; CRISPR/Cas technology; Cell Line; Cells; Centrosome; Chromosomal Instability; Clinical; Clinical Trials; Color; Combination Drug Therapy; Complex; Data; Development; Diagnosis; Disease; Disease Progression; Down-Regulation; European; Excision; Experimental Designs; Genes; Genetic; Genome Stability; Genotype; Goals; Growth; Hospitals; Impairment; Individual; Interphase; Kinesin; Knock-out; Knowledge; Medical center; Methods; Mitosis; Modality; Modeling; Molecular; Motor; Neoplasm Metastasis; Nigeria; Nuclear; Oncogenic; Outcome; Patient Self-Report; Patients; Population; Prognostic Marker; Proteins; Race; Research; Risk; Risk Factors; Role; Sampling; Signal Transduction; Specimen; Stains; Stratification; Survival Analysis; System; Testing; Therapeutic; Time; Treatment Protocols; Tumor Biology; Tumor Markers; Universities; Validation; WNT Signaling Pathway; Woman; Xenograft Model; Xenograft procedure; aurora kinase A; base; beta catenin; biobank; breast cancer progression; chemotherapy; chromatin modification; cohort; disorder risk; druggable target; effective therapy; follow-up; genome-wide; improved; improved outcome; indexing; individualized medicine; inhibitor/antagonist; malignant breast neoplasm; migration; mortality; novel; novel therapeutics; patient biomarkers; patient population; personalized medicine; pre-clinical; precision medicine; preclinical study; prognostic; prognostic tool; prognostic value; protein biomarkers; racial difference; racial disparity; specific biomarkers; success; triple-negative invasive breast carcinoma; tumor; tumor progression

ABSTRACT! African ancestry is a risk factor for worse outcomes in triple-negative breast cancer (TNBC). Nevertheless, prognostic tools and treatment regimens are no different for African American (AA) than European American (EA) TNBC patients. Personalizing medicine for AA TNBC patients has been hindered by the fact that this population is highly admixed, so self-reported race often does not accurately reflect African genetic ancestry. There is also a dearth of studies that have analyzed tumor biomarkers and clinical outcomes using ancestry- genotyped TNBC specimens. Furthermore, few preclinical TNBC studies consider race in experimental design, and AA TNBC patients are markedly underrepresented in clinical trials. A critical barrier to progress in improving outcomes for AA TNBC patients is a lack of prognostic tools and treatment modalities that have been precisely tailored to this patient population. The broad, long-range goal of this project is to enable development of precision medicine for AA TNBC patients by advancing knowledge of the utility of nuclear HSET (nHSET) as a prognostic biomarker for AA TNBCs as well as the molecular mechanisms of racial disparities in TNBC aggressiveness and how they can be targeted. Our lab has uncovered that HSET more strongly promotes proliferation and migration of AA than EA TNBC cell lines. In addition, nHSET independently predicts poor outcomes in AA but not EA TNBCs, but this must be validated after accounting for percent African genetic ancestry in multivariable survival models and in native African TNBCs. Our proposed project has three aims. First, the proportion of African genetic ancestry will be determined for a large cohort of TNBC patient samples acquired from US, and Nigeria and we will determine if nHSET can serve as a racial disparity biomarker for the stratification of TNBCs after adjusting for their percent African genetic ancestry. Second, since HSET and MYH9 are nuclear binding partners that may assist in chromatin modification to amplify oncogenic Wnt/β-catenin signaling and MYC expression (which we have found is enriched in AA compared with EA TNBCs), we will characterize racial differences in the HSET-MYH9-MYC axis in TNBCs using patient-derived samples and correlate these racial distinctions to differences in genomic stability in TNBCs. We will employ multi-colored lenti- CRISPR-Cas9 system for knocking out key genes in this axis in AA/EA cell lines to test if the HSET-MYH9-MYC axis drives tumor aggressiveness more strongly in AA than in EA TNBCs. In Aim 3, the value of a promising commercially available HSET inhibitor will be tested in xenograft models of AA and EA TNBC patient-derived cells. Thus, this study will test the hypothesis that nHSET is a novel therapeutically actionable biomarker with greater value for AA than EA TNBC patients that drives TNBC progression and chemoresistance more strongly in AA than EA TNBC patients. The impact of this project will be to advance knowledge of prognostic biomarkers, molecular mechanisms of disease aggressiveness, and effective treatment regimens for AA TNBC patients. !

抽象的！ 非洲血统是三阴性乳腺癌（TNBC）中结果差的危险因素。尽管如此， 非裔美国人（AA）的预后工具和治疗方案与欧洲美国人没有什么不同 （EA）TNBC患者。为AA TNBC患者个性化医学已受到这一事实的阻碍 人口高度混合，因此自我报告的种族通常不能准确反映非洲遗传血统。 还有一项研究死亡，已使用祖先分析了肿瘤生物标志物和临床结果 基因分型TNBC标本。此外，很少有临床前TNBC研究考虑实验设计中的种族， 在临床试验中，AA TNBC患者的代表性明显不足。进步的关键障碍 改善AA TNBC患者的预后是缺乏预后工具和治疗方式 精确地针对该患者人群量身定制。该项目的广泛，远程目标是实现发展 通过推进核HSET（NHSET）效用的AA TNBC患者精密医学 AA TNBC的预后生物标志物以及TNBC种族分布的分子机制 侵略性及其目标。我们的实验室发现了HSES更强烈地促进 与EA TNBC细胞系相比，AA的增殖和迁移。此外，NHSET独立预测贫困 AA的结果，但不是TNBC，但这必须在占非洲遗传百分比之后得到验证 多变量生存模型和非洲原住民TNBC中的祖先。我们提议的项目有三个目标。 首先，将确定大量TNBC患者样本的非洲遗传血统比例 从我们和尼日利亚获取，我们将确定NHSET是否可以作为种族差异生物标志物 调整非洲遗传血统百分比后，TNBC的分层。第二，自HSES和MYH9以来 是可以帮助染色质修饰以扩增致癌的Wnt/β-catenin的核结合伴侣 信号传导和MYC表达（与EA TNBC相比，我们发现的AA中富集了AA），我们将 使用患者衍生的样本和 这些种族区别与TNBC中基因组稳定性的差异相关。我们将采用多色四旬斋 CRISPR-CAS9系统用于在AA/EA细胞系中敲除此轴的关键基因以测试HSES-MYH9-MYC是否 与在EA TNBC中相比，AA在AA中更强烈地驱动肿瘤攻击性。在AIM 3中，承诺的价值 将在AA和EA TNBC衍生的AA和EA的特征模型中测试市售HSES抑制剂 细胞。这是这项研究将检验的假设，即NHSET是一种新型的热可操作的生物标志物， 与EA TNBC患者相比，AA的价值更大 在AA中，比EA TNBC患者。该项目的影响是提高对预后生物标志物的了解， AA TNBC患者的疾病侵袭性和有效治疗方案的分子机制。 呢