Evaluation of molecular determinants of racial disparity in triple-negative breast cancer

三阴性乳腺癌种族差异的分子决定因素评估

• 批准号: 9925054
• 负责人: Dipali Sharma
• 金额: $ 37.46万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-17 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925054
• 关键词: African American; American; Automobile Driving; Biological; Biological Assay; Biological Markers; Breast Cancer Cell; Breast Cancer Detection; Breast Cancer Patient; Clinical; Collection; Dasatinib; Data; Dichloroacetate; Drug Screening; Drug Targeting; EP300 gene; ERBB2 gene; Epoxy Compounds; Esters; Estrogen Receptors; European; Evaluation; Exhibits; Growth; Half-Life; Health Services Accessibility; In Vitro; Label; Lead; Libraries; Luciferases; Magnolia grandiflora; Mammary Neoplasms; Methane; Microarray Analysis; Modeling; Molecular; Nature; Neoplasm Metastasis; Oncogenes; Oncogenic; Oncoproteins; Oral Administration; Outcome; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Pharmacology; Phase II Clinical Trials; Progesterone Receptors; Prognostic Marker; Proteins; Regimen; Regulation; Role; STK11 gene; Sampling; Signal Transduction; Socioeconomic Status; Stage at Diagnosis; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Coactivator with PDZ-Binding Motif; Treatment Efficacy; Tumor Bank; Tumor Suppressor Proteins; United States Food and Drug Administration; Up-Regulation; Verteporfin; Woman; Xenograft Model; addiction; analog; base; breast cancer progression; clinical predictors; cohort; disparity reduction; epithelial to mesenchymal transition; honokiol; improved; in silico; in vivo; in vivo evaluation; insight; lipophilicity; malignant breast neoplasm; migration; mortality; novel; oncogene addiction; pre-clinical; preclinical study; racial disparity; receptor expression; triple-negative invasive breast carcinoma; tumor; tumor progression; tumor xenograft; upstream kinase

PROJECT SUMMARY/ABSTRACT Triple negative breast cancer (TNBC) is a very aggressive subtype with limited therapeutic options. Intriguingly, women of African American (AA) origin have much higher TNBC-related mortality rates compared to European American (EA) women. This difference is evident even after adjusting for socioeconomic status and access to care, indicating a biological basis. TNBC tumors in AA women exhibit higher rate of growth and metastasis in comparison to TNBC in EA women. There is an urgent need to understand the molecular mechanisms involved in aggressive progression and increased metastatic potential of AA-TNBC. In our preliminary studies, we observed that AA-TNBC cells have higher invasion and migration potential in comparison to EA-TNBC cells showing inherently aggressive nature of AA-TNBC. In a preliminary screen, we found that a large percentage of AA-TNBC tumors exhibit loss-of-tumor suppressor Liver Kinase B1 (LKB1) in comparison to EA-TNBC tumors. Our preliminary microarray studies also found that LKB1-loss in AA-TNBC results in activation of oncoproteins- YAP and TAZ. Our data suggest that with inherent loss of LKB1, AA-TNBC gain `an oncogenic input' in the form of activated YAP-TAZ signaling. Using in vitro studies, clinical AA-TNBC and EA-TNBC samples and patient-derived xenograft (PDX) models, we will test our hypothesis that inherent LKB1-loss in AA-TNBC results in activation of oncogenic YAP-TAZ signaling leading to aggressive progression and increased metastatic potential of AA-TNBC. Our novel findings also suggest that AA-TNBC tumors may be vulnerable to therapeutic strategies directed at YAP-TAZ inhibition. Based on our strong preliminary data, we will investigate how loss of LKB1 in AA-TNBC might lead to acquisition of higher YAP-TAZ, and drive growth and metastasis of AA-TNBC cells. We will also analyze AA-TNBC and EA-TNBC tumors to establish LKB1-loss and elevated YAP-TAZ as biomarkers of aggressive progression of AA-TNBC. We will utilize these biological insights to test and propose safe and effective therapeutic strategies to target AA-TNBC. Using patient-derived xenograft (PDX) models, we propose to investigate whether AA-TNBCs are particularly susceptible to YAP-TAZ inhibition strategies and whether currently clinically available drugs (screened from a drug library) can be repurposed to target YAP-TAZ in AA-TNBC. Secondly, we plan to examine whether Honokiol, a natural compound from Magnolia grandiflora, (selected from a screen of known bioactive compounds) and its novel analogs have the potential to inhibit YAP-TAZ in AA-TNBC. Our studies will provide new understanding how loss-of-LKB1 and gain-of-YAP-TAZ in AA-TNBC form a relentless axis that drives AA-TNBC. These studies will provide novel insight into molecular mechanisms underlying racial disparity in TNBC and provide a novel set of biomarkers and potential drug-targets to develop novel ways to reduce the disparity in clinical outcome of AA and EA TNBC patients.

项目总结/摘要 三阴性乳腺癌（TNBC）是一种非常具有侵袭性的亚型，治疗选择有限。有趣的是， 非洲裔美国人（AA）女性的TNBC相关死亡率比欧洲女性高得多。 美国（EA）女性即使在调整了社会经济地位和获得 护理，表示生物学基础。AA女性中的TNBC肿瘤在AA女性中表现出更高的生长和转移率。 与EA女性中的TNBC相比。有迫切需要了解参与的分子机制， AA-TNBC的侵袭性进展和增加的转移潜力。在初步研究中，我们观察到 AA-TNBC细胞与EA-TNBC细胞相比具有更高的侵袭和迁移潜力， AA-TNBC固有的侵略性。在初步筛选中，我们发现很大比例的AA-TNBC 与EA-TNBC肿瘤相比，EA-TNBC肿瘤表现出肿瘤抑制因子肝激酶B1（LKB 1）的丧失。我们 初步的微阵列研究还发现，AA-TNBC中LKB 1的缺失导致癌蛋白-雅普的活化 和TAZ。我们的数据表明，由于LKB 1的固有损失，AA-TNBC以下列形式获得“致癌输入”： 激活YAP-TAZ信号。使用体外研究，临床AA-TNBC和EA-TNBC样品和患者来源的TNBC样品在体外被检测。 在异种移植物（PDX）模型中，我们将检验我们的假设，即AA-TNBC中的固有LKB 1损失导致LKB 1的激活。 致癌YAP-TAZ信号传导导致AA-TNBC的侵袭性进展和增加的转移潜力。 我们的新发现还表明，AA-TNBC肿瘤可能容易受到针对肿瘤的治疗策略的影响。 YAP-TAZ抑制。基于我们强有力的初步数据，我们将研究AA-TNBC中LKB 1的丢失如何可能 导致获得更高YAP-TAZ，并驱动AA-TNBC细胞的生长和转移。我们还将分析 AA-TNBC和EA-TNBC肿瘤，以建立LKB 1丢失和升高的YAP-TAZ作为侵袭性肿瘤的生物标志物。 AA-TNBC的进展。我们将利用这些生物学见解来测试和提出安全有效的治疗方法， 针对AA-TNBC的战略。使用患者来源的异种移植物（PDX）模型，我们建议研究是否 AA-TNBC对YAP-TAZ抑制策略特别敏感，并且无论目前临床上是否可用， 药物（从药物库中筛选的）可以重新用于靶向AA-TNBC中的YAP-TAZ。其次，我们计划 检查是否Honokaline，一种来自Magnolia grandiflora的天然化合物，（从已知的筛选中选出） 生物活性化合物）及其新型类似物具有抑制AA-TNBC中的YAP-TAZ的潜力。我们的研究将 提供了新的理解，如何在AA-TNBC中失去LKB 1和获得YAP-TAZ形成一个无情的轴， AA-TNBC这些研究将为TNBC种族差异的分子机制提供新的见解 并提供了一组新的生物标志物和潜在的药物靶点，以开发新的方法来减少 AA和EA TNBC患者的临床结果。