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: 10158022
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158022
• 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; 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; Tumor Bank; Tumor Suppressor Proteins; United States Food and Drug Administration; Up-Regulation; Verteporfin; Woman; addiction; analog; base; breast cancer progression; clinical predictors; cohort; disparity reduction; efficacy evaluation; epithelial to mesenchymal transition; honokiol; improved; in silico; in vivo; in vivo evaluation; insight; lipophilicity; malignant breast neoplasm; migration; mortality; novel; oncogene addiction; patient derived xenograft model; pre-clinical; preclinical study; racial disparity; receptor expression; therapeutically effective; 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.

项目摘要/摘要 三阴性乳腺癌(TNBC)是一种侵袭性很强的亚型，治疗选择有限。有趣的是， 与欧洲人相比，非裔美国人(AA)女性的TNBC相关死亡率要高得多 美国(EA)女性。即使在调整了社会经济地位和获得 关怀，表明有生物学基础。再生障碍性贫血患者的TNBC肿瘤生长和转移率较高 电针女性与TNBC的比较。迫切需要了解与之相关的分子机制。 AA-TNBC的侵袭性进展和转移潜能增加。在我们的初步研究中，我们观察到 AA-TNBC细胞比EA-TNBC细胞具有更高的侵袭和迁移能力 AA-TNBC的内在攻击性。在初步筛查中，我们发现很大比例的AA-TNBC 与EA-TNBC肿瘤相比，肿瘤表现为肿瘤丢失抑制因子肝激酶B1(LKB1)。我们的 初步的微阵列研究还发现，AA-TNBC中LKB1的缺失会导致癌蛋白-YAP的激活 和TAZ。我们的数据表明，随着LKB1的固有丢失，AA-TNBC获得了以以下形式的致癌输入 激活了YAP-TAZ信号。使用体外研究，临床AA-TNBC和EA-TNBC样本和患者来源 异种移植(PDX)模型，我们将检验我们的假设，即AA-TNBC中固有的LKB1缺失导致激活 致癌的YAP-TAZ信号导致AA-TNBC的侵袭性进展和转移潜能增加。 我们的新发现也表明AA-TNBC肿瘤可能对针对以下目标的治疗策略敏感 YAP-TAZ抑制作用。基于我们强大的初步数据，我们将调查LKB1在AA-TNBC中的损失可能 导致获得较高的YAP-TAZ，并推动AA-TNBC细胞的生长和转移。我们还将分析 AA-TNBC和EA-TNBC肿瘤建立LKB1缺失和YAP-TAZ升高作为侵袭性生物标志物 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(PDX)模型，我们建议调查 AA-TNBCs对YAP-TAZ抑制策略特别敏感，目前是否可用于临床 在AA-TNBC中，药物(从药物库中筛选)可以被重新用于靶向YAP-TAZ。其次，我们计划 检查和厚朴酚，一种来自厚朴的天然化合物，(选自已知的 生物活性化合物)及其新的类似物具有抑制AA-TNBC中YAP-TAZ的潜力。我们的研究将 提供对AA-TNBC中LKB1的损失和YAP-TAZ的增益如何形成驱动的无情轴的新理解 AA-TNBC。这些研究将为解释TNBC中种族差异的分子机制提供新的见解 并提供了一套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 再生障碍性贫血和电针刺五加患者的临床转归。

项目成果

The power of small changes: Comprehensive analyses of microbial dysbiosis in breast cancer.

• DOI: 10.1016/j.bbcan.2019.04.001
• 发表时间: 2019-04
• 期刊: Biochimica et biophysica acta. Reviews on cancer
• 作者: Parida S;Sharma D
• 通讯作者: Sharma D

Concomitant activation of ETS-like transcription factor-1 and Death Receptor-5 via extracellular signal-regulated kinase in withaferin A-mediated inhibition of hepatocarcinogenesis in mice.

• DOI: 10.1038/s41598-017-18190-4
• 发表时间: 2017-12-20
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Kuppusamy P;Nagalingam A;Muniraj N;Saxena NK;Sharma D
• 通讯作者: Sharma D

Gut colonization with an obesity-associated enteropathogenic microbe modulates the premetastatic niches to promote breast cancer lung and liver metastasis.

• DOI: 10.3389/fimmu.2023.1194931
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Hyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen by coordinating a crosstalk between Med1, miR205 and ErbB.

• DOI: 10.1038/s41523-021-00314-9
• 发表时间: 2021-08-13
• 期刊: NPJ breast cancer
• 影响因子: 5.9
• 作者: Nagalingam A;Siddharth S;Parida S;Muniraj N;Avtanski D;Kuppusamy P;Elsey J;Arbiser JL;Győrffy B;Sharma D
• 通讯作者: Sharma D

Triple Negative Breast Cancer: A Mountain Yet to Be Scaled Despite the Triumphs.

• DOI: 10.3390/cancers13153697
• 发表时间: 2021-07-23
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Wu Q;Siddharth S;Sharma D
• 通讯作者: Sharma D