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.

项目概要 三阴性乳腺癌 (TNBC) 的侵袭性部分归因于其转移性 行为、快速复发的倾向以及对标准护理的低反应 化疗。 TNBC 与最差的预后和临床结果相关， 尤其是非裔美国 (AA) 女性。有趣的是，TNBC 的发病率更高 AA 女性的这一比例是白人女性 (CA) 女性的 2 倍以上 有同样的疾病。这些与种族相关的结果差异仍然很差 理解，即使在控制了社会经济和治疗差异之后仍然很重要，并且 表明肿瘤生物学差异对癌症结果的这些差异的影响。 我们发现 YB1（一种多功能基因）是 TNBC 差异的潜在生物驱动因素。 AA 女性。我们还发现 YB1 的致癌信号传导可能在激活 AA 女性中 TNBC 的侵袭转移级联和治疗耐药性。 YB1表达 AA 肿瘤中的水平显着较高，并且与较差的总体生存率密切相关 AA TNBC 患者。 YB1 核定位/磷酸化 (S102) 也与 癌症干细胞表型，以及 AA 来源的 TNBC 肿瘤对化疗的耐药性。基于 基于这一强有力的证据，我们提出了总体假设：YB1 致癌信号传导 是造成 AA 和 CA TNBC 疾病结果差异的一个主要因素 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 YB1 信号轴的变化。我们的建议还将尝试更好地阐明 遗传、环境、社会经济和生活方式之间复杂的相互作用 促进观察到的差异，最终目标是开发和实施更多 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 YB1 信号传导（表达、磷酸化和 核定位）对 TNBC 细胞系和 AA 肿瘤致瘤性和化疗耐药性的影响 起源; (2) 确定针对 YB1 的新型联合疗法对缓解症状的影响 AA TNBC 肿瘤的进展和转移； (3) 判断YB1信令是否可以 基于转录组学和预测 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，我们的创新提案将为该领域做出巨大贡献 癌症差异，特别是对于患有 TNBC 的 AA 女性，并将确定新的基于 YB1 的 针对这种对 AA 女性有不同影响的毁灭性癌症的治疗方案。