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: 10632100
• 负责人: Ritu Aneja
• 金额: --
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632100
• 关键词: Accounting; Address; Adjuvant; African; African American; African American population; African ancestry; American; Automobile Driving; Binding; Biological; Biological Markers; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; Cell Line; Cells; Centrosome; Chemoresistance; 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; Institution; 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; Proliferating; Proteins; Qualifying; Race; Research; Risk Factors; Role; Sampling; Side; Signal Transduction; Specimen; Stains; Stratification; Survival Analysis; System; Testing; Therapeutic; Treatment Protocols; Tumor Biology; Tumor Markers; Universities; Validation; WNT Signaling Pathway; Woman; Xenograft Model; Xenograft procedure; aggressive breast cancer; aggressive therapy; aurora kinase A; beta catenin; biobank; breast cancer progression; chemotherapy; chromatin modification; cohort; druggable target; effective therapy; follow-up; genome-wide; improved; improved outcome; indexing; individualized medicine; inhibitor; 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; risk prediction; 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) 预后较差的一个危险因素。 非裔美国人 (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 患者对 AA TNBC 患者的个性化医疗受到了这一事实的阻碍。 人口高度混合，因此自我报告的种族往往不能准确反映非洲的遗传血统。 还缺乏使用祖先分析生物标志物肿瘤和临床结果的研究。 此外，很少有临床前 TNBC 研究在实验设计中考虑种族因素， 和 AA TNBC 患者在临床试验中的代表性明显不足，这是取得进展的关键障碍。 改善 AA TNBC 患者的预后是缺乏已被证实的预后工具和治疗方式 该项目的广泛、长期目标是促进发展。 通过提高核 HSET (nHSET) 实用性的知识，为 AA TNBC 患者提供精准医疗 AA TNBC 的预后生物标志物以及 TNBC 种族差异的分子机制 我们的实验室发现，HSET 更强烈地促进攻击性。 AA 的增殖和迁移能力优于 EA TNBC 细胞系此外，nHSET 的独立预测能力较差。 AA 而非 EA TNBC 的结果，但这必须在考虑非洲遗传百分比后进行验证 我们提出的项目有三个目标。 首先，将确定大量 TNBC 患者样本中非洲遗传血统的比例 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 调整非洲遗传血统百分比后的 TNBC 分层 其次，自 HSET 和 MYH9 以来。 是核结合伴侣，可能有助于染色质修饰以放大致癌 Wnt/β-连环蛋白 信号传导和 MYC 表达（我们发现与 EA TNBC 相比，AA 中的表达更丰富），我们将 使用患者来源的样本描述 TNBC 中 HSET-MYH9-MYC 轴的种族差异 我们将使用多色慢病毒将这些种族差异与 TNBC 基因组稳定性差异联系起来。 CRISPR-Cas9 系统，用于敲除 AA/EA 细胞系中该轴的关键基因，以测试 HSET-MYH9-MYC 是否有效 与 EA TNBC 相比，轴在 AA 中更强烈地驱动肿瘤侵袭性。 市售 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 因此，本研究将检验 nHSET 是一种具有新颖作用的治疗性生物标志物的假设。 AA 比 EA 对 TNBC 患者具有更大的价值，更强烈地推动 TNBC 进展和化疗耐药 该项目的影响将是增进对预后生物标志物的了解， 疾病侵袭性的分子机制以及 AA TNBC 患者的有效治疗方案。 ！

项目成果

Digital image analysis and machine learning-assisted prediction of neoadjuvant chemotherapy response in triple-negative breast cancer.

数字图像分析和机器学习辅助预测三阴性乳腺癌新辅助化疗反应。

• 发表时间: 2024-01-18
• 作者: Fisher, Timothy B;Saini, Geetanjali;Rekha, T S;Krishnamurthy, Jayashree;Bhattarai, Shristi;Callagy, Grace;Webber, Mark;Janssen, Emiel A M;Kong, Jun;Aneja, Ritu
• 通讯作者: Aneja, Ritu

Quadruple-negative breast cancer: novel implications for a new disease.

四阴性乳腺癌：一种新疾病的新含义。

• 发表时间: 2020
• 作者: Bhattarai, Shristi;Saini, Geetanjali;Gogineni, Keerthi;Aneja, Ritu
• 通讯作者: Aneja, Ritu

Exosomal Metabolic Signatures Are Associated with Differential Response to Neoadjuvant Chemotherapy in Patients with Breast Cancer.

外泌体代谢特征与乳腺癌患者对新辅助化疗的差异反应相关。

• 发表时间: 2022-05-10
• 影响因子: 5.6
• 作者: Joshi, Shriya;Garlapati, Chakravarthy;Bhattarai, Shristi;Su, Yixin;Rios;Deep, Gagan;Torres, Mylin A;Aneja, Ritu
• 通讯作者: Aneja, Ritu

SARS-CoV-2 Infection in Cancer Patients: Effects on Disease Outcomes and Patient Prognosis.

癌症患者中的 SARS-CoV-2 感染：对疾病结果和患者预后的影响。

• 发表时间: 2020-11-05
• 影响因子: 5.2
• 作者: Seth, Gaurav;Sethi, Saira;Bhattarai, Shristi;Saini, Geetanjali;Singh, Chandra Bhushan;Aneja, Ritu
• 通讯作者: Aneja, Ritu

Polyploid giant cancer cell characterization: New frontiers in predicting response to chemotherapy in breast cancer.

多倍体巨型癌细胞特征：预测乳腺癌化疗反应的新领域。

• 发表时间: 2022-06
• 影响因子: 14.5
• 作者: Saini, Geetanjali;Joshi, Shriya;Garlapati, Chakravarthy;Li, Hongxiao;Kong, Jun;Krishnamurthy, Jayashree;Reid, Michelle D;Aneja, Ritu
• 通讯作者: Aneja, Ritu