Diversity Supplement Grant: TRIM37 is a genetic determinant of racial disparity in metastatic TNBC patients

多样性补充补助金：TRIM37 是转移性 TNBC 患者种族差异的遗传决定因素

• 批准号: 10592946
• 负责人: Sanchita Bhatnagar
• 金额: $ 4.9万
• 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/10592946
• 关键词: African American; Alleles; Anoikis; Antibodies; Antisense Oligonucleotides; Biological; Blood Circulation; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast Cancer cell line; Clinical; Data; Dependence; Disease; Distant; Engineering; Ethnic Origin; FOLR1 gene; Gene Expression Profile; Genes; Genetic; Genetic Determinism; Grant; Growth; Head Start Program; In Vitro; Incidence; Infiltration; Metastatic breast cancer; Neoplasm Metastasis; Oncogenic; Outcome; Pathway interactions; Patients; Phenotype; Prognosis; Proteins; Race; Relapse; Resistance; Risk; Single Nucleotide Polymorphism; Survival Rate; TRIM Motif; Testing; Therapeutic; Tumor Tissue; Woman; base; cancer cell; cancer health disparity; clinical investigation; clinically relevant; experience; genetic variant; health care disparity; high risk; in vivo; mortality; mouse model; nanoparticle; novel; overexpression; patient derived xenograft model; racial disparity; triple-negative invasive breast carcinoma; tumor growth

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.

非裔美国人（AA）女性患有侵袭性转移性三阴性乳腺癌亚型 （TNBC）与其他种族相比，死亡率更高。尽管医疗保健差距 导致AA女性预后不良，但TNBC差异的种族特异性遗传成分不能被 排除了因此，TNBC差异背后的种族隔离遗传决定因素仍然是一个未满足的临床问题。 需要的这个项目是建立在我们的新发现，表明一个致癌的三方基序含有 蛋白37（TRIM 37）蛋白使AA女性易患高度侵袭性TNBC。我们证明：（1） TRIM 37与TNBC患者的转移表型和总生存期相关，2）TRIM 37在TNBC患者中表达。 在AA女性的乳腺和TNBC肿瘤组织中相对于其他种族具有更高的水平，3）TRIM 37- 相关的单核苷酸多态性与AA女性中TRIM 37的高表达相关，4）TRIM 37 调节参与转移级联反应的基因和途径，如促进循环中的存活，5）AA 与非AA TNBC细胞系相比，TNBC细胞在体外显示出对致癌TRIM 37的依赖性增加 和体内，6）TRIM 37消耗减少转移鼠模型中的远处浸润和生长 使用基于靶向纳米颗粒的TRIM 37特异性反义寡核苷酸递送的抑制降低了 TNBC肿瘤生长。基于这些发现，我们假设AA女性中TRIM 37水平较高， 通过创造一个转移前的小生境，使潜在的癌细胞“领先”。这一假设将在三个 明确的目标。在目标1中，我们将评估TRIM 37等位基因变异，我们已经确定，通过小- 基于失巢凋亡抗性的规模表型筛选。我们还将确定TRIM 37等位基因的机制， 通过比较TRIM 37风险等位基因和参考等位基因的生物学活性来确定变体。在目标2中，我们将比较 并以种族依赖性方式对比TRIM 37对TNBC转移潜力的相对贡献。我们 还将跟踪TRIM 37及其转录特征与种族，转移发生率， 以及使用来自TNBC患者的无病组织和肿瘤组织的患者存活率。在目标3中，我们将比较 TRIM 37耗尽和TRIM 37过表达的种族特异性乳腺和TNBC细胞的转移潜力 使用自发转移鼠模型。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TRIM 37的治疗平台 和人源化鼠模型。总之，拟议的研究将证明TRIM 37是一种遗传性的， 与AA女性TNBC高风险相关的变异，概念验证结果将建立临床 抑制TRIM 37与TNBC治疗的相关性。