A novel racial disparity marker for risk prediction in triple negative breast cancer patients

用于三阴性乳腺癌患者风险预测的新型种族差异标记

• 批准号: 8997736
• 负责人: Ritu Aneja
• 金额: $ 20.75万
• 依托单位: NOVAZOI THERANOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997736
• 关键词: Accounting; Adverse effects; African American; American; Attention; Binding; Biological Assay; Biological Markers; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; Cell Nucleus; Cell Survival; Centrosome; Clinical; Confocal Microscopy; Cytotoxic Chemotherapy; Data; Databases; Development; Disease; European; Evaluation; Formalin; Gene Expression; Gene Expression Profile; Goals; Hormone Receptor; Human; Immunohistochemistry; Importins; Kinesin; Lead; Malignant Neoplasms; Mediator of activation protein; Metastatic to; Methods; Minority; Molecular; Neoplasm Metastasis; Nuclear; Nuclear Import; Nuclear Localization Signal; Nuclear Pore Complex Proteins; Outcome; Paraffin Embedding; Pathway interactions; Patients; Pharmacologic Substance; Pilot Projects; Predictive Value; Progression-Free Survivals; Protein Isoforms; Proteins; RNA; Race; Recurrence; Relative (related person); Risk; Risk Marker; Running; Sampling; Small Business Technology Transfer Research; Solutions; Somatic Cell; Staining method; Stains; Statistical Methods; Subgroup; Testing; Therapeutic; Time; Tissue Microarray; Tissues; Tumor Biology; Validation; Woman; base; cancer cell; cancer type; cell motility; clinical efficacy; cohort; combat; early onset; ethnic difference; health disparity; high risk; improved; inhibitor/antagonist; malignant breast neoplasm; matrigel; mortality; novel; nucleocytoplasmic transport; overexpression; prognostic; prognostic value; public health relevance; racial difference; racial disparity; receptor; targeted treatment; therapeutic target; triple-negative invasive breast carcinoma; tumor

 DESCRIPTION (provided by applicant): Breast cancers in African American (AA) women are characterized by earlier onset, higher aggressiveness, more extensive metastases, and increased mortality rates compared to those in European American (EA) women. This breast cancer-related health disparity is partly due to the fact that AA women are more likely than EA women to develop a particularly aggressive breast cancer subtype, called Triple-Negative Breast Cancer (TNBC). TNBC is characterized by fast progression to metastasis and high mortality rates. Furthermore, there are no targeted therapies for TNBC. Critical barriers to progress in improving outcomes for AA TNBC patients are (i) a lack of reliable risk-predictive biomarkers that can identify TNBCs at high risk of progressing rapidly to metastatic disease, and (ii) targeted therapies for TNBCs. Since tumor biology between AA and EA women with TNBC can vary greatly, the optimal way to combat TNBC may differ between AA and EA patients. Thus, it is critical to identify key biomarkers that may have special therapeutic and prognostic value within certain ethnic subgroups. We recently found that AA TNBC patients were ~3 times as likely as EA TNBC patients to have high nuclear levels of HSET, a centrosome-clustering kinesin. We found that higher nuclear HSET levels were also associated with more aggressive tumor features and decreased metastasis-free survival. As a result, nuclear HSET may be a racial disparity biomarker in TNBC. Furthermore, HSET may be a valuable target to suppress metastasis because we found that TNBC cell migration was inhibited by HSET knockdown. Overexpression of Npap60L, a nucleoporin isoform, is known to suppress nuclear import. In a search of publically-available gene expression databases, we found that AA TNBCs have lower Npap60L levels than EA TNBCs. Therefore, we hypothesize that low Npap60L levels in AA TNBCs promotes nuclear accumulation of HSET. Our novel paradigm that ethnic differences in nuclear transport pathways promote different subcellular localization of HSET, a key mediator of metastasis, is a groundbreaking conceptual advancement. It holds translational promise not only in metastatic risk prediction but also in providing an anti- metastatic therapeutic target for TNBC patients with high nuclear HSET. AIM 1 will establish nuclear HSET as a racial disparity biomarker by evaluating its nuclear expression as a predictor of a) metastasis, b) poor progression-free survival, and c) poor overall survival in AA TNBC patients. AIM 2 will test whether racial differences in the levels of a nucleoporin protein (Npap60L) involved in nuclear import promotes nuclear retention of HSET in AA TNBCs. The overall impact of this project will be to validate HSET as a racial disparity biomarker and mechanistically define the Npap60L-HSET axis as a new pathway that can be targeted to thwart metastatic onset in AA TNBC patients and alleviate ethnic breast cancer-related health disparity.

 描述（由申请人提供）：与欧洲裔美国人（EA）女性相比，非洲裔美国人（AA）女性的乳腺癌特征为发病早、侵袭性高、转移更广泛和死亡率增加。这种与乳腺癌相关的健康差异部分是由于AA女性比EA女性更有可能发展出一种特别具有侵袭性的乳腺癌亚型，称为三阴性乳腺癌（TNBC）。TNBC的特征在于快速进展为转移和高死亡率。此外，没有针对TNBC的靶向疗法。在改善AA TNBC患者的结局方面取得进展的关键障碍是（i）缺乏可靠的风险预测生物标志物，其可以识别快速进展为转移性疾病的高风险TNBC，以及（ii）TNBC的靶向治疗。由于患有TNBC的AA和EA女性之间的肿瘤生物学可能存在很大差异，因此AA和EA患者对抗TNBC的最佳方法可能有所不同。因此，确定在某些种族亚组中可能具有特殊治疗和预后价值的关键生物标志物至关重要。我们最近发现AA TNBC患者具有高核水平的HSET（一种中心体聚集驱动蛋白）的可能性是EA TNBC患者的约3倍。我们发现细胞核HSET水平越高，肿瘤的侵袭性越强，无转移生存率越低。因此，核HSET可能是TNBC中的种族差异生物标志物。此外，HSET可能是抑制转移的有价值的靶标，因为我们发现TNBC细胞迁移被HSET敲低抑制。已知Npap 60 L（核孔蛋白同种型）的过表达抑制核输入。在公开可用的基因表达数据库的搜索中，我们发现AA TNBC具有比EA TNBC更低的Npap 60 L水平。因此，我们假设AA TNBC中的低Npap 60 L水平促进HSET的核积累。我们的新范式，核转运途径的种族差异促进不同的亚细胞定位的HSET，转移的关键介质，是一个突破性的概念进步。它不仅在转移风险预测方面，而且在为具有高核HSET的TNBC患者提供抗转移治疗靶标方面具有转化前景。AIM 1将通过评估核HSET的核表达作为AA TNBC患者中a）转移、B）不良无进展生存期和c）不良总生存期的预测因子来确立核HSET作为种族差异生物标志物。AIM 2将测试参与核输入的核孔蛋白（Npap 60 L）水平的种族差异是否促进AA TNBC中HSET的核保留。该项目的总体影响将是验证HSET作为种族差异生物标志物，并将Npap 60 L-HSET轴机械地定义为一种新的途径，可以靶向阻止AA TNBC患者的转移性发作并减轻种族乳腺癌相关的健康差异。