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

 描述(申请人提供)：与欧洲裔美国人(EA)女性相比，非裔美国人(AA)女性乳腺癌的特点是发病更早，侵袭性更强，转移范围更广，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，称为三阴性乳腺癌(TNBC)。TNBC的特点是进展快，转移快，死亡率高。此外，目前还没有针对TNBC的靶向治疗。在改善再障TNBC患者预后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记物来识别快速进展为转移性疾病的高风险TNBCs，以及(Ii)TNBCs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是至关重要的。我们最近发现，AA TNBC患者比EA TNBC患者有高水平的HSET核水平的可能性~3倍，HSET是一种中心体聚集的动蛋白。我们发现，较高的核HSET水平也与更具侵袭性的肿瘤特征和降低的无转移生存率有关。因此，核HSET可能是TNBC的种族差异生物标志物。此外，HSET可能是一个有价值的抑制转移的靶点，因为我们发现HSET基因敲除后，TNBC细胞的迁移受到抑制。核孔蛋白亚型NPap60L的过表达被认为可以抑制核进口。在对公开可用的基因表达数据库的搜索中，我们发现AA TNBCs的NPap60L水平低于EA TNBCs。因此，我们假设AA TNBCs中低水平的NPap60L促进HSET的核积聚。我们的新范式认为，核运输途径的种族差异促进了HSET的不同亚细胞定位，HSET是转移的关键介质，这是一个开创性的概念进步。它不仅在转移风险预测方面具有翻译前景，而且在为核HSET高的TNBC患者提供抗转移治疗靶点方面也具有前景。目的1将核HSET作为种族差异的生物标志物，通过评估其核表达作为AA TNBC患者a)转移、b)无进展生存不良和c)总体生存不良的预测指标。目的2将测试参与核进口的核孔蛋白(NPap60L)水平的种族差异是否促进再生障碍性TNBCs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记物的有效性，并机械地将NPap60L-HSET轴定义为一种新的途径，可以靶向阻止AA TNBC患者的转移发病，并缓解与种族乳腺癌相关的健康差距。

 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.