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（申请人提供）：与欧洲裔美国 (EA) 女性相比，非裔美国 (AA) 女性乳腺癌的特点是发病更早、侵袭性更高、转移更广泛、死亡率更高。这种与乳腺癌相关的健康差异部分是由于 AA 女性比 EA 女性更有可能患上一种特别侵袭性的乳腺癌亚型，即三阴性乳腺癌 (TNBC)。 TNBC 的特点是进展快、转移快、死亡率高。此外，TNBC 尚无靶向治疗方法。改善 AA TNBC 患者预后的关键障碍是 (i) 缺乏可靠的风险预测生物标志物，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差异很大，因此 AA 和 EA 患者对抗 TNBC 的最佳方法可能有所不同。因此，确定在某些种族亚群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 患者的 HSET（一种中心体聚集驱动蛋白）核水平较高，可能性约为 EA TNBC 患者的 3 倍。我们发现，较高的核 HSET 水平还与更具侵袭性的肿瘤特征和降低的无转移生存率相关。因此，核 HSET 可能是 TNBC 中的种族差异生物标志物。此外，HSET可能是抑制转移的一个有价值的靶点，因为我们发现TNBC细胞迁移受到HSET敲低的抑制。 Npap60L（一种核孔蛋白亚型）的过度表达已知会抑制核输入。在对公开基因表达数据库的搜索中，我们发现 AA TNBC 的 Npap60L 水平低于 EA TNBC。因此，我们假设 AA TNBC 中的低 Npap60L 水平会促进 HSET 的核积累。我们的新范式是核转运途径的种族差异促进 HSET（转移的关键介质）的不同亚细胞定位，这是一个突破性的概念进步。它不仅在转移风险预测方面具有转化前景，而且还为具有高核 HSET 的 TNBC 患者提供抗转移治疗靶点。 AIM 1 将通过评估其核表达作为 AA TNBC 患者 a) 转移、b) 不良无进展生存率和 c) 不良总体生存率的预测因子，将核 HSET 确立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 (Npap60L) 水平的种族差异是否会促进 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，并从机制上将 Npap60L-HSET 轴定义为一种新途径，可用于阻止 AA TNBC 患者的转移发作并缓解种族乳腺癌相关的健康差异。