Role of YB1 in health disparities in triple negative breast cancer

项目摘要 三重阴性乳腺癌的侵袭性在一定程度上是由于它们的转移。 行为、迅速复发的倾向和对标准护理的低反应 化疗。TNBCs与最差的预后和临床结局有关， 尤其是非裔美国人(AA)女性。有趣的是，TNBC的发病率更高 与白人美国人(CA)女性相比，AA女性的比例高出2倍以上 都有同样的疾病。这些与种族相关的结果差异，仍然很差 即使在控制了社会经济和治疗差异之后，也是显著的 提示肿瘤生物学上的差异对癌症结果的这些差异的贡献。 我们确定YB1是一种多功能基因，可能是导致中国人TNBC差异的潜在生物学因素。 AA级的女人。我们还发现YB1的致癌信号可能在激活过程中起主要作用 再生障碍性贫血患者TNBC侵袭转移级联反应与治疗耐药YB1表达 AA肿瘤中的水平显著较高，并与较差的总体生存密切相关 在再障TNBC患者中。YB1核定位/磷酸化(S102)也与 AA来源的TNBC肿瘤中的肿瘤干细胞表型和化疗耐药性。基座 根据这一强有力的证据，我们提出了YB1致癌信号的首要假设 是AA和CA TNBC疾病结局差异的主要因素 病人。这一假说将通过研究生物学和临床意义来解决。 YB1信号轴在TNBC差异中的作用。我们的建议也将试图更好地澄清 遗传学、环境、社会经济学和生活方式之间的复杂相互作用可能 为观察到的差异做出贡献，最终目标是开发和实施更多 有效的以人口为基础的战略，以改善这一弱势群体的健康公平。 我们的具体目标将：(1)确定YB1信号的影响(表达、磷酸化和 核定位)在再障TNBC细胞系和肿瘤的致瘤性和耐药性中的作用 来源；(2)确定针对YB1的新型联合疗法对缓解 AA TNBC肿瘤的进展和转移；以及(3)决定YB1信号是否可以 基于转录组学和药物耐药性预测TNBC中的种族差异和化疗耐药性 免疫组织化学。 我们非常有信心，我们的创新建议将为 癌症差异，特别是患有TNBC的AA女性，并将确定新的基于YB1的 这种对AA女性有不同影响的毁灭性癌症的治疗选择。

Project Summary The aggressiveness of triple negative breast cancers (TNBCs) is, in part, due to their metastatic behavior, propensity to recur rapidly and dismal low response to standard-of-care chemotherapies. TNBCs are associated with the worst prognosis and clinical outcomes, especially in African American (AA) women. Interestingly, the incidence rate of TNBC is more than 2-fold higher in AA women, compared with their Caucasian American (CA) counterparts who have the same disease. These racial-associated disparities in outcomes, that remain poorly understood, are significant even after controlling for socioeconomic and treatment variations, and suggest the contribution of differences in tumor biology to these disparities in cancer outcomes. We identified YB1, a multifunctional gene, as a potential biological driver of TNBC disparities in AA women. We also found that the oncogenic signaling of YB1 may play a major role in activating the invasion-metastasis cascade and therapy resistance of TNBC in AA women. YB1 expression levels are significantly higher in AA tumors and are strongly associated with poorer overall survival in AA TNBC patients. YB1 nuclear localization/phosphorylation (S102) is also correlated with cancer stem cell phenotype, and resistance to chemotherapy in TNBC tumors of AA origin. Based on this strong evidence, we developed the overarching hypothesis that YB1 oncogenic signaling is a major contributing factor to differences in disease outcomes between AA and CA TNBC patients. This hypothesis will be addressed by investigating the biologic and clinical significance of YB1 signaling axis in TNBC disparities. Our proposal will also attempt to better elucidate the complex interactions between genetics, environment, socioeconomics and lifestyle that may contribute to the observed differences with the ultimate goal of developing and implementing more efficacious population-based strategies to improve health equity for this vulnerable population. Our specific aims will (1) Determine the impact of YB1 signaling (expression, phosphorylation and nuclear localization) in tumorigenicity and chemoresistance in TNBC cell lines and tumors of AA origin; (2) Determine the impact of novel combination therapies targeting YB1 to alleviate progression and metastasis of AA TNBC tumors; and (3) Determine whether YB1 signaling can predict racial disparities and chemoresistance in TNBC, based on transcriptomics and immunohistochemistry. We are very confident that our innovative proposal will make great contributions to the field of cancer disparities, especially for AA women with TNBC, and will identify new YB1-based therapeutic options for this devastating cancer that is disparately affecting AA women.