TRIM37 is a genetic determinant of racial disparity in metastatic TNBC patients

TRIM37 是转移性 TNBC 患者种族差异的遗传决定因素

• 批准号: 10512666
• 负责人: Sanchita Bhatnagar
• 金额: $ 34.75万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512666
• 关键词: TRIM37; genetic; determinant; racial; disparity

African American (AA) women presents with aggressive metastatic subtype of triple negative breast cancer (TNBC) compared to other ethnicities and experience greater mortality rates. Although health care disparities contribute to poor prognosis in AA women but a race-specific genetic component to TNBC disparity cannot be ruled out. Thus, racially-segregated genetic determinant underlying TNBC disparity remains an unmet clinical need. This project is built upon our novel findings suggesting that an oncogenic tripartite motif-containing protein 37 (TRIM37) protein predisposes AA women to highly aggressive TNBC. We demonstrate that 1) TRIM37 associates with metastatic phenotype and overall survival in TNBC patients, 2) TRIM37 is expressed at higher level in the breast and TNBC tumor tissue of AA women relative to other races, 3) TRIM37- associated single nucleotide polymorphism correlates with high TRIM37 expression in AA women, 4) TRIM37 regulates genes and pathways involved in metastasis cascade, such as promoting survival in circulation, 5) AA TNBC cells showed increased dependency on oncogenic TRIM37 compared to non-AA TNBC cell lines in vitro and in vivo, 6) TRIM37 depletion reduces distant infiltration and growth in metastasis murine model 7) TRIM37 inhibition using targeted nanoparticles-based delivery of TRIM37-specific antisense oligonucleotides reduces TNBC tumor growth. Based on these findings, we hypothesize that higher TRIM37 levels in AA women gives a would-be cancer cell a “head start” by creating a pre-metastatic niche. This hypothesis will be tested in three specific aims. In aim 1, we will evaluate TRIM37-allelic variants, that we have already identified, through small- scale phenotypic screen based on anoikis resistance. We will also determine the mechanism of TRIM37-allelic variants by comparing the biological activity of TRIM37 risk and reference alleles. In aim 2, we will compare and contrast the relative contribution of TRIM37 to TNBC metastatic potential in race-dependent manner. We will also track association between TRIM37 and its transcriptional signatures with race, metastasis incidence, and patient's survival using disease-free and tumor tissue from TNBC patients. In aim 3, we will compare the metastatic potential of TRIM37-depleted and TRIM37 overexpressing race-specific breast and TNBC cells using spontaneous metastasis murine models. Finally, we will test newly engineered TNBC selective therapeutic platform to inhibit TRIM37 using spontaneous metastasis, race-specific patient-derived xenografts and humanized murine models. Together, the proposed studies will demonstrate that TRIM37 is a genetic variant associated with high TNBC risk in AA women and proof-of-concept results will establish the clinical relevance of inhibiting TRIM37 for TNBC treatment.

非裔美国 (AA) 女性患有侵袭性转移亚型三阴性乳腺癌 （TNBC）与其他种族相比，死亡率更高，尽管医疗保健存在差异。 导致 AA 女性预后不良，但 TNBC 差异的种族特异性遗传成分无法被解释 因此，TNBC 差异背后的种族隔离遗传决定因素仍然是一个未得到解决的临床问题。 该项目是建立在我们的新发现之上的，即含有致癌的三方基序。 蛋白 37 (TRIM37) 蛋白使 AA 女性易患高度侵袭性 TNBC 1)。 TRIM37 与 TNBC 患者的转移表型和总生存率相关，2) TRIM37 表达 与其他种族相比，AA 女性的乳腺和 TNBC 肿瘤组织中的水平较高，3) TRIM37- 相关单核苷酸多态性与 AA 女性中 TRIM37 的高表达相关，4) TRIM37 调节参与转移级联的基因和途径，例如促进循环中的存活，5) AA 与非 AA TNBC 细胞系相比，TNBC 细胞在体外表现出对致癌 TRIM37 的依赖性增强 在体内，6) TRIM37 耗竭减少了转移小鼠模型中的远处浸润和生长 7) TRIM37 使用基于靶向纳米颗粒的 TRIM37 特异性反义寡核苷酸递送的抑制作用可减少 基于这些发现，我们发现 AA 女性中较高的 TRIM37 水平可以促进 TNBC 肿瘤的生长。 潜在的癌细胞通过创建转移前的生态位而“领先”这一假设将在三个阶段进行检验。 在目标 1 中，我们将通过小分子评估我们已经确定的 TRIM37 等位基因变体。 基于失巢凋亡抗性的规模表型筛选我们还将确定 TRIM37 等位基因的机制。 在目标 2 中，我们将比较 TRIM37 风险等位基因和参考等位基因的生物活性。 并以种族依赖性方式对比 TRIM37 对 TNBC 转移潜力的相对贡献。 还将追踪 TRIM37 及其转录特征与种族、转移发生率、 在目标 3 中，我们将比较 TNBC 患者的无病组织和肿瘤组织。 TRIM37 耗尽和 TRIM37 过表达种族特异性乳腺癌和 TNBC 细胞的转移潜力 最后，我们将测试新设计的 TNBC 选择性。 使用自发转移、种族特异性患者来源的异种移植物抑制 TRIM37 的治疗平台 和人源化小鼠模型一起，拟议的研究将证明 TRIM37 是一种遗传基因。 与 AA 女性高 TNBC 风险相关的变异和概念验证结果将建立临床 抑制 TRIM37 与 TNBC 治疗的相关性。