HSET as a racial disparity biomarker for TNBC patients

抽象！ 非洲血统是三阴性乳腺癌(TNBC)预后更差的危险因素。不过， 非洲裔美国人(AA)的预后工具和治疗方案与欧洲裔美国人没有什么不同 (EA)TNBC患者。AA TNBC患者的个性化药物一直受到阻碍，因为这一事实 人口高度混杂，因此自我报告的种族往往不能准确反映非洲人的遗传祖先。 使用祖先来分析肿瘤生物标记物和临床结果的研究也很少。 对TNBC标本进行基因分型。此外，很少有临床前TNBC研究在实验设计中考虑种族， 再障TNBC患者在临床试验中的代表性明显不足。取得进展的关键障碍 改善再障TNBC患者的预后是缺乏预后工具和治疗方式的，这些工具和治疗方式已经 为这些患者量身定做的。这个项目的广泛、长期的目标是使发展 提高对核HSET(NHSET)作为AA-TNBC患者的应用的认识 再生障碍性鼻咽癌的预后生物标记物及TNBC种族差异的分子机制 攻击性以及如何将其作为目标。我们实验室发现，HSET更有力地促进了 AA细胞系的增殖和迁移能力高于EA TNBC细胞系。此外，nHSET独立预测较差 AA而不是EA TNBCs的结果，但这必须在占非洲遗传百分比后进行验证 多变量生存模型和非洲本土TNBCs的祖先。我们提出的项目有三个目标。 首先，将确定大量TNBC患者样本的非洲遗传祖先比例 从美国和尼日利亚获得，我们将确定nHSET是否可以作为种族差异的生物标志物 对非洲人的遗传血统进行调整后，TNBCs的分层。第二，由于HSET和Myh9 是核结合伙伴，可能有助于染色质修饰以放大致癌的WNT/β-连环蛋白 信号和MYC表达(我们发现与EA TNBCs相比，AA富含MYC)，我们将 使用患者来源的样本和研究TNBCs中HSET-Myh9-MYC轴的种族差异 将这些种族差异与TNBCs基因组稳定性的差异联系起来。我们将采用多种颜色的Lenti- 用CRISPR-Cas9系统敲除AA/EA细胞系这一轴上的关键基因以检测HSET-Myh9-MYC AXIS在AA中推动肿瘤侵袭性比在EA TNBCs中更强。在目标3中，一个有希望的 商业上可用的HSET抑制剂将在AA和EA TNBC患者来源的异种移植模型中进行测试 细胞。因此，这项研究将检验nHSET是一种新的具有治疗作用的生物标记物的假设。 与EA TNBC患者相比，AA对推动TNBC进展和化疗耐药性更强的患者具有更大的价值 再生障碍性贫血患者高于电针TNBC患者。该项目的影响将是促进对预后生物标记物的了解， 疾病侵袭性的分子机制，以及对再障TNBC患者的有效治疗方案。 好了！

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. !