Role of YB1 in health disparities in triple negative breast cancer

项目摘要 三阴性乳腺癌（TNBC）的侵袭性部分是由于它们的转移性肿瘤。 行为、快速复发倾向和对标准治疗的低反应 化疗TNBC与最差的预后和临床结果相关， 尤其是在非洲裔美国人（AA）妇女中。有趣的是，TNBC的发病率更高， AA女性中，与他们的白人美国人（CA）相比， 有同样的疾病。这些与种族相关的结果差异， 即使在控制了社会经济和治疗差异后， 表明肿瘤生物学的差异对癌症结果的这些差异的贡献。 我们确定YB 1是一种多功能基因，是TNBC差异的潜在生物驱动因素， 戒酒会的女人。我们还发现YB 1的致癌信号传导可能在激活细胞凋亡中起主要作用。 AA妇女中TNBC的侵袭-转移级联和治疗抗性。yb 1表达 AA肿瘤中的水平显著更高，并且与较差的总体生存率密切相关。 在AA TNBC患者中。YB 1核定位/磷酸化（S102）也与 癌症干细胞表型和AA来源的TNBC肿瘤对化疗的抗性。基于 基于这一强有力的证据，我们提出了YB 1致癌信号传导的总体假设， 是AA和CA TNBC之间疾病结局差异的主要促成因素 患者这一假设将通过研究生物学和临床意义来解决 YB 1信号轴在TNBC差异中的作用。我们的提案还将试图更好地阐明 遗传学、环境、社会经济学和生活方式之间复杂的相互作用， 有助于观察到的差异，最终目标是制定和实施更多的 有效的基于人口的战略，以改善这一弱势群体的健康公平。 我们的具体目标是（1）确定YB 1信号传导（表达，磷酸化和 核定位）在TNBC细胞系和AA肿瘤的致瘤性和化学抗性中的作用 （2）确定靶向YB 1的新型联合治疗对缓解 AA TNBC肿瘤的进展和转移;和（3）确定YB 1信号传导是否可以 根据转录组学预测TNBC的种族差异和化疗耐药性， 免疫组化 我们坚信，我们的创新建议将为该领域做出巨大贡献。 癌症差异，特别是AA女性与TNBC，并将确定新的YB 1为基础的 这种毁灭性的癌症是严重影响AA妇女的治疗选择。

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.