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

• 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
• 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

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.

摘要 背景：乳腺癌仍然是全世界女性癌症相关死亡的主要原因 尽管我们越来越广泛地了解生物学，风险因素，和基因组景观， 疾病化学预防是降低乳腺癌发病率和死亡率的有效策略 癌这种方法的可行性和前景是由对选择性雌激素的持续临床兴趣来说明的 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，西美坦）， 乳腺癌的化学预防。不幸的是，这些干预措施有副作用， 对乳腺癌ER阴性亚型的活性（例如，基底样乳腺癌）。因此，一个安全和 对不同亚型的乳腺癌有效的廉价化学预防干预仍然 令人向往该临床前研究项目的首要目标是获取体内证据， 葱属植物中一种很有前途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），使用啮齿动物模型显示出与基底样和 管腔型人类乳腺癌。在人类相关动物中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在先前的首次人体试验中耐受良好。 采用间歇给药方案的干预性研究。已发表的工作，包括我们实验室的工作， 已经证明了DATS对基底样和管腔型人乳腺癌细胞系的活性， 体外，以及它们的异种移植物和体内癌症干细胞（bCSC）群体。流行病学研究也 表明大蒜和洋葱的饮食摄入量与乳腺癌的风险呈负相关。 这个建议的机制方面是非常新颖的，围绕着一个仍然知之甚少的问题。 转录因子，叉头盒Q1（FoxQ 1）。受益于TCGA的RNA-Seq数据 数据库和通过靶向基因表达谱，我们已经确定了FoxQ 1的新靶点，包括 腊肠犬同源物1（DACH 1）和单羧酸转运蛋白1（MCT 1）。DACH 1是一种细胞命运 决定因子和肿瘤抑制因子，而MCT 1在调节代谢过程中具有致癌作用。 在癌细胞中重新编程。我们最近发表的工作表明FoxQ 1是直接转录的 DACH 1的阻遏物，因此FoxQ 1的表达与DACH 1的表达呈负相关。 人乳腺癌（TCGA）。另一方面，FoxQ 1的表达与 MCT 1。我们还发现，DATS处理抑制FoxQ 1和MCT 1的表达，但诱导DACH 1的表达。 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，FoxQ 1/MCT 1轴对乳腺癌进展的贡献及其在癌症中的潜在作用 DATS的化学预防作用尚待阐明。因此，机械论的研究逻辑上集中在 FoxQ 1及其新的下游靶点（DACH 1和MCT 1）在乳腺癌化学预防中的作用 DATS。假设：我们假设口服DATS可预防基底样和 在人类相关的啮齿动物模型中通过抑制受 FoxQ 1（bCSC的自我更新和从糖酵解到氧化磷酸化的代谢转换）。 具体目的：（1）确定DATS用于以下的化学预防的体内功效：（a）基底样乳腺癌 （B）使用大鼠模型的管腔型乳腺癌;（2）确定 FoxQ 1/DACH 1轴在使用人基底样和腔型乳腺癌的DATS抑制bCSC中的作用 （3）确定FoxQ 1/MCT 1轴在代谢重编程中的作用及其被DATS抑制 使用代表人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DAT处理的小鼠和大鼠的肿瘤组织（目的1）将用于确定体内肿瘤转移。 FoxQ 1/DACH 1和FoxQ 1/MCT 1轴在DATS化学预防乳腺癌中意义 重要性：化学预防功效的临床前证据对于证明DATS的临床试验是至关重要的。 乳腺癌患者。第一个具体目标是直接测试化学预防基底细胞样和 使用良好表征的啮齿动物模型，通过DATS给药治疗腔型乳腺癌。拟议 机制研究可以区分在未来临床研究中可能有用的药效学生物标志物 关于DATS最后，进一步了解FoxQ 1在乳腺癌中的作用可能最终导致新的乳腺癌发生。 这种异质性疾病的治疗方法。