The Role of FoxQ1 in Breast Cancer Chemoprevention by Allium Constituents - R01CA219180

FoxQ1 在葱成分预防乳腺癌中的作用 - R01CA219180

基本信息

批准号：
10374763
负责人：
Shivendra Singh
金额：
$ 35.08万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374763
关键词：
Address Allium Allium Vegetable Allium cepa Animal Model Aromatase Inhibitors Attenuated Biology Breast Cancer Cell Breast Cancer Patient Breast Cancer Risk Factor Breast Cancer cell line Cancer Etiology Cell model Cells Cessation of life Chemical Models Chemoprevention Chemopreventive Agent Clinical Clinical Research Clinical Trials Data Databases Development Dietary Phytochemical Dietary intake Disease Dose Down-Regulation ERBB2 gene Estrogen Receptors Estrogen receptor negative Exemestane Exhibits FOXQ1 gene Future Garlic Gene Expression Profile Gene Expression Profiling Genetic Genetic Transcription Genomics Glycolysis Goals Homologous Gene Human In Vitro Incidence Intervention Intervention Studies Knowledge Laboratories Lead Malignant Neoplasms Mammary Neoplasms Mediating Metabolic Methylnitrosourea Modeling Molecular Morbidity - disease rate Mus Oncogenic Oral Administration Oxidative Phosphorylation Population Pre-Clinical Model Process Proteins Publishing Rattus Regulation Reproducibility Research Research Project Grants Risk Factors Risk Reduction Rodent Rodent Model Role Schedule Selective Estrogen Receptor Modulators Specimen Tamoxifen Testing The Cancer Genome Atlas Tissue Microarray Transcription Repressor Transgenic Mice Tumor Suppressor Proteins Tumor Tissue Woman Work Xenograft Model Xenograft procedure base breast cancer progression cancer cell cancer chemoprevention cancer stem cell cell growth chromatin immunoprecipitation clinical development design diallyl trisulfide efficacious intervention epidemiologic data epidemiology study experimental study first-in-human human model in vivo interest malignant breast neoplasm mortality mouse model neoplastic cell novel novel therapeutics overexpression pharmacodynamic biomarker pre-clinical pre-clinical research prevent primary endpoint self-renewal side effect transcription factor transcriptome sequencing

项目摘要

ABSTRACT Background: Breast cancer remains a leading cause of cancer-related deaths among women worldwide despite our increasingly broader understanding of the biology, risk factors, and genomic landscape of the disease. Chemoprevention signifies a meaningful strategy for reducing the morbidity and mortality from breast cancer. Feasibility and promise of this approach is illustrated by continued clinical interest in selective estrogen receptor (ER) modulators (e.g., tamoxifen), and more recently, aromatase inhibitors (e.g., exemestane) for chemoprevention of luminal-type breast cancers. Unfortunately, these interventions have side effects and lack activity against ER-negative subtypes of breast cancer (e.g., basal-like breast cancer). Therefore, a safe and inexpensive chemopreventive intervention efficacious against different subtypes of breast cancer is still desirable. The overarching goal of this preclinical research project is to acquire in vivo evidence for chemopreventive efficacy of a highly promising dietary phytochemical (diallyl trisulfide; DATS) from Allium vegetables (e.g., garlic) using rodent models exhibiting significant molecular overlap with basal-like and luminal-type human breast cancers. In vivo evidence of chemopreventive efficacy in human-relevant animal models is a prerequisite for initiation of clinical trials of DATS, which was well-tolerated in a prior first-in-human interventional study with intermittent dosing schedule. Published work, including that from our laboratory, already demonstrates activity of DATS against basal-like and luminal-type human breast cancer cell lines in vitro, and their xenografts and cancer stem cell (bCSC) populations in vivo. Epidemiological studies have also suggested an inverse association between dietary intake of garlic and onions and the risk of breast cancer. The mechanistic aspects of this proposal are exceedingly novel and revolve around a still poorly understood transcription factor, Forkhead box Q1 (FoxQ1). Benefitted by access to the RNA-Seq data from TCGA database and through targeted gene expression profiling, we have identified novel targets of FoxQ1, including Dachshund homolog 1 (DACH1) and monocarboxylate transporter 1 (MCT1). DACH1 is a cell fate determination factor and tumor suppressor, whereas MCT1 has an oncogenic role in regulation of metabolic reprogramming in cancer cells. Our recently published work indicates that FoxQ1 is a direct transcriptional repressor of DACH1, and consequently FoxQ1 expression is inversely associated with that of DACH1 in human breast cancers (TCGA). On the other hand, FoxQ1 expression is positively associated with that of MCT1. We also found that DATS treatment suppresses FoxQ1 and MCT1 expression but induces DACH1 protein in breast cancer cells in vitro. However, the in vivo relevance of these cellular findings is still unclear. Likewise, the contribution of FoxQ1/MCT1 axis to breast cancer progression and its potential role in cancer chemoprevention by DATS are yet to be elucidated. Therefore, the mechanistic studies logically focus on the role of FoxQ1 and its novel downstream targets (DACH1 and MCT1) in breast cancer chemoprevention by DATS. Hypothesis: We hypothesize that oral administration of DATS prevents development of basal-like and luminal-type breast cancer in human-relevant rodent models by suppressing oncogenic processes regulated by FoxQ1 (self-renewal of bCSC and metabolic switch from glycolysis to oxidative phosphorylation). Specific Aims: (1) Determine the in vivo efficacy of DATS for chemoprevention of: (a) basal-like breast cancer using a transgenic mouse model, and (b) luminal-type breast cancer using a rat model; (2) Determine the role of FoxQ1/DACH1 axis in bCSC inhibition by DATS using human basal-like and luminal-type breast cancer cells; and (3) Determine the role of FoxQ1/MCT1 axis in metabolic reprogramming and its inhibition by DATS using cellular models and breast tumor tissue arrays representative of human basal-like and luminal subtypes. The tumor tissues from control and DATS-treated mice and rats (aim 1) will be used to determine the in vivo significance of FoxQ1/DACH1 and FoxQ1/MCT1 axes in breast cancer chemoprevention by DATS. Significance: Preclinical evidence of chemopreventive efficacy is essential to justify clinical trial of DATS in breast cancer patients. The first specific aim directly tests the possibility of chemoprevention of basal-like and luminal-type breast cancer by DATS administration using well-characterized rodent models. The proposed mechanistic studies may distinguish pharmacodynamic biomarker(s) potentially useful in future clinical studies with DATS. Finally, further understanding of the role of FoxQ1 in breast cancer may ultimately lead to novel therapies for this heterogeneous disease.

抽象的背景：乳腺癌仍然是全球女性癌症相关死亡的主要原因尽管我们对生物学、风险因素和基因组景观的了解越来越广泛疾病。化学预防是降低乳腺癌发病率和死亡率的有意义的策略癌症。对选择性雌激素的持续临床兴趣说明了这种方法的可行性和前景受体（ER）调节剂（例如他莫昔芬），以及最近的芳香酶抑制剂（例如依西美坦）管腔型乳腺癌的化学预防。不幸的是，这些干预措施有副作用并且缺乏针对 ER 阴性乳腺癌亚型（例如基底样乳腺癌）的活性。因此，一个安全且对不同亚型乳腺癌有效的廉价化学预防干预措施仍然存在理想的。该临床前研究项目的总体目标是获取体内证据葱中一种极具前景的膳食植物化学物质（二烯丙基三硫化物；DATS）的化学预防功效蔬菜（例如大蒜）使用啮齿动物模型表现出与基础样和显着分子重叠管腔型人类乳腺癌。人类相关动物化学预防功效的体内证据模型是启动 DATS 临床试验的先决条件，DATS 在之前的首次人体试验中具有良好的耐受性间歇性给药方案的介入研究。已发表的作品，包括我们实验室的作品，已经证明 DATS 对基底样和管腔型人类乳腺癌细胞系具有活性体外，以及它们的异种移植物和体内癌症干细胞（bCSC）群体。流行病学研究还表明大蒜和洋葱的饮食摄入量与乳腺癌风险之间存在负相关。该提案的机械方面非常新颖，并且围绕着一个仍然知之甚少的问题转录因子，叉头盒 Q1 (FoxQ1)。受益于访问 TCGA 的 RNA-Seq 数据数据库并通过靶向基因表达谱分析，我们确定了 FoxQ1 的新靶点，包括腊肠犬同源物 1 (DACH1) 和单羧酸转运蛋白 1 (MCT1)。 DACH1是细胞命运决定因子和肿瘤抑制因子，而 MCT1 在代谢调节中具有致癌作用癌细胞中的重编程。我们最近发表的工作表明 FoxQ1 是直接转录的 DACH1 的阻遏蛋白，因此 FoxQ1 的表达与 DACH1 的表达呈负相关人类乳腺癌（TCGA）。另一方面，FoxQ1 表达与 MCT1。我们还发现 DATS 处理抑制 FoxQ1 和 MCT1 表达，但诱导 DACH1 体外乳腺癌细胞中的蛋白质。然而，这些细胞发现的体内相关性仍不清楚。同样，FoxQ1/MCT1 轴对乳腺癌进展的贡献及其在癌症中的潜在作用 DATS 的化学预防尚未阐明。因此，机理研究逻辑上集中于 FoxQ1 及其新下游靶标（DACH1 和 MCT1）在乳腺癌化学预防中的作用数据传输。假设：我们假设口服 DATS 可以阻止基底样细胞和通过抑制致癌过程调节人类相关啮齿动物模型中的管腔型乳腺癌 FoxQ1（bCSC 的自我更新和从糖酵解到氧化磷酸化的代谢转换）。具体目标： (1) 确定 DATS 对以下化学预防的体内功效： (a) 基底样乳腺癌使用转基因小鼠模型，和（b）使用大鼠模型的管腔型乳腺癌； (2)确定角色使用人基底样和腔型乳腺癌通过 DATS 抑制 FoxQ1/DACH1 轴在 bCSC 中的作用细胞； (3)确定FoxQ1/MCT1轴在代谢重编程中的作用及其被DATS的抑制使用代表人类基底样和管腔亚型的细胞模型和乳腺肿瘤组织阵列。来自对照和 DATS 处理的小鼠和大鼠（目标 1）的肿瘤组织将用于确定体内 FoxQ1/DACH1 和 FoxQ1/MCT1 轴在 DATS 乳腺癌化学预防中的意义。意义：化学预防功效的临床前证据对于证明 DATS 临床试验的合理性至关重要乳腺癌患者。第一个具体目标直接测试基础样和化学预防的可能性使用特征良好的啮齿动物模型通过 DATS 管理来治疗管腔型乳腺癌。拟议的机制研究可以区分在未来临床研究中可能有用的药效生物标志物与 DATS。最后，进一步了解 FoxQ1 在乳腺癌中的作用可能最终会带来新的发现针对这种异质性疾病的治疗方法。