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

非裔美国人(AA)女性表现为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。尽管医疗保健方面的差距 导致再生障碍性贫血妇女预后不良，但导致TNBC差异的种族特有的遗传成分不能 排除了。因此，导致TNBC差异的种族隔离的基因决定因素仍然是一个未得到满足的临床问题。 需要。这个项目是建立在我们的新发现基础上的，该发现表明一个致癌的三方基序包含 蛋白37(TRIM37)蛋白使AA妇女易患高度侵袭性的TNBC。我们演示了1) TRIM37与TNBC患者的转移表型和总生存期有关，2)TRIM37的表达 AA女性乳腺和TNBC肿瘤组织中的水平高于其他种族，3)TRIM37- 关联的单核苷酸多态与再生障碍性贫血患者中TRIM37的高表达相关，4)TRIM37 调节参与转移级联反应的基因和途径，如促进循环中的生存，5)AA 与非AA的TNBC细胞株相比，TNBC细胞对致癌基因TRIM37的依赖性增加 在体内，缺失TRIM37基因可减少转移模型小鼠的远处侵袭和生长 使用靶向纳米颗粒递送TRIM37特异性反义寡核苷酸的抑制作用 TNBC肿瘤生长。基于这些发现，我们假设再生障碍性贫血女性体内较高的TRIM37水平会导致 潜在的癌细胞通过创造一个转移前的利基来“先行一步”。这一假设将在三年内得到检验 明确的目标。在目标1中，我们将评估我们已经确定的TRIM37等位基因变体，通过小的- 基于失巢阻力的标度表型筛选。我们还将确定TRIM37-等位基因的机制 通过比较TRIM37风险等位基因和参考等位基因的生物活性来确定突变。在目标2中，我们将比较 并以种族依赖的方式比较TRIM37对TNBC转移潜能的相对贡献。我们 还将跟踪TRIM37及其转录特征与种族、转移发病率、 使用TNBC患者的无病组织和肿瘤组织来评估患者的生存情况。在目标3中，我们将比较 TRIM37缺失和过表达种族特异性乳腺和TNBC细胞的转移潜能 采用小鼠自发转移模型。最后，我们将测试新设计的TNBC选择性 利用种族特异性异种移植抑制TRIM37的治疗平台 和人性化的小鼠模型。总之，拟议的研究将证明TRIM37是一种基因 AA女性中与高TNBC风险相关的变异和概念验证结果将确立临床 抑制TRIM37与TNBC治疗的相关性

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.