Role of YB1 in health disparities in triple negative breast cancer

YB1 在三阴性乳腺癌健康差异中的作用

• 批准号: 10655943
• 负责人: KHALID SOSSEY-ALAOUI
• 金额: $ 48.16万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-12 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655943
• 关键词: Address; Affect; African American; Age; Animals; Area; Behavior; Biological; Biological Markers; Breast Cancer Patient; Breast Cancer cell line; Breast Diseases; Cancer Death Rates; Chemoresistance; Clinical; Combined Modality Therapy; Complex; Data; Data Set; Death Rate; Diagnosis; Disease; Disease Outcome; Disparity; Disparity population; Environment; Ethnic Population; Formalin; General Population; Genes; Genetic; Goals; Hospitals; Human; Immunohistochemistry; In Vitro; Incidence; Invaded; Life Style; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Medical center; Modality; Molecular; Neoadjuvant Therapy; Neoplasm Metastasis; Nuclear; Ohio; Oncogenic; Outcome; Paraffin Embedding; Pathologic; Patients; Phenotype; Phosphorylation; Play; Population; Primary Neoplasm; Prognosis; Publishing; Race; Recurrence; Resistance; Role; Serine; Signal Pathway; Signal Transduction; Site; Socioeconomic Status; Testing; Therapeutic; Tissue Embedding; Tumor Biology; Tumorigenicity; Variant; Vulnerable Populations; Woman; Xenograft procedure; black women; cancer health disparity; cancer stem cell; caucasian American; chemotherapy; clinically significant; cohort; differential expression; effectiveness evaluation; genetic manipulation; health disparity; health equity; improved; in vivo; innovation; malignant breast neoplasm; neoplastic cell; novel; outcome disparities; population based; potential biomarker; predicting response; predictive marker; progression marker; public health relevance; racial disparity; racial population; response; response biomarker; small molecule; sociodemographic factors; socioeconomics; standard of care; success; targeted treatment; therapeutic target; therapy resistant; transcriptomics; triple-negative invasive breast carcinoma; tumor

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.

项目摘要 三重负乳腺癌（TNBC）的侵略性部分是由于它们的转移 行为，快速重复出现的倾向以及对护理标准的低反应 化学疗法。 TNBC与最坏的预后和临床结局有关 特别是在非裔美国人（AA）妇女中。有趣的是，TNBC的发病率更多 与她们的高加索裔美国人（CA）相比，AA女性高2倍 患有相同的疾病。这些与种族相关的结果差异，这些差异仍然很差 理解，即使控制了社会经济和治疗差异，也很重要 表明肿瘤生物学差异对癌症结局的这些差异的贡献。 我们将YB1（一种多功能基因）确定为TNBC差异的潜在生物学驱动力 妇女。我们还发现，YB1的致癌信号在激活中可能起主要作用 TNBC在AA妇女中的入侵 - 米达级联和治疗性。 YB1表达 AA肿瘤的水平明显更高，并且与总生存期较差密切相关 在AA TNBC患者中。 YB1核定位/磷酸化（S102）也与 癌症干细胞表型和AA起源TNBC肿瘤中化学疗法的抗性。基于 在这个有力的证据上，我们提出了YB1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因素 患者。该假设将通过研究生物学和临床意义来解决 TNBC差异中的YB1信号轴的。我们的建议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的复杂互动，可能 为观察到的差异做出贡献，其最终目标是开发和实施更多 有效的基于人口的策略，以改善这一脆弱人群的健康公平。 我们的具体目的将（1）确定YB1信号传导的影响（表达，磷酸化和 核定位）在TNBC细胞系和AA肿瘤中的致瘤性和化学抗性中 起源; （2）确定针对YB1的新型组合疗法的影响 AA TNBC肿瘤的进展和转移； （3）确定YB1信号是否可以 基于转录组学和 免疫组织化学。 我们非常有信心我们的创新提议将为该领域做出巨大贡献 癌症差异，特别是对于具有TNBC的AA妇女，将确定新的基于YB1的妇女 这种毁灭性癌症的治疗选择对AA妇女产生了不同的影响。