Project 3: Alcohol-Associated Toxicity and Genomic Instability of Mammary Stem Cells

项目3：酒精相关的毒性和乳腺干细胞的基因组不稳定性

• 批准号: 10540967
• 负责人: XIAOHE YANG
• 金额: $ 18.65万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540967
• 关键词: Acetaldehyde; Alcohol consumption; Alcohols; Animal Model; Animals; Breast Cancer Cell; Breast Cancer Risk Factor; Breast Cancer cell line; Breast Carcinogenesis; Breast Epithelial Cells; CD44 gene; Cancer Etiology; Cancer cell line; Cancerous; Cell Line; Cells; Chromosome abnormality; Chromosomes; DNA Damage; DNA Repair; DNA Repair Disorder; Data; Detection; Development; Diet; ERBB2 gene; Early Diagnosis; Female; Flow Cytometry; Frequencies; Gene Dosage; Gene Mutation; Genetic; Genome; Genomic Instability; Genomics; Hematopoietic stem cells; Histopathology; Human; ITGB3 gene; Impairment; Injury; Karyotype determination procedure; Knock-out; Lead; Lesion; Liquid substance; Liver; Malignant - descriptor; Mammary Neoplasms; Mammary Tumorigenesis; Mammospheres; Mediating; Mediator of activation protein; Methodology; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Mutate; Mutation; Neoplasm Metastasis; Pathogenesis; Pathway interactions; Play; Premalignant Cell; Prevention; Process; Recurrence; Reporting; Risk; Role; STAT3 gene; Signal Transduction; Stem Cell Research; Stem cell transplant; TNFSF11 gene; TP53 gene; Testing; Tissues; Toxic effect; Transgenic Animals; Tumor Suppressor Proteins; Up-Regulation; alcohol abuse therapy; alcohol effect; alcohol prevention; alcohol research; alcohol response; base; beta catenin; cancer initiation; cancer stem cell; carcinogenesis; cell transformation; cell type; cellular targeting; chromosomal location; clinically relevant; comparative genomic hybridization; diagnostic biomarker; experience; genotoxicity; in vitro Model; in vivo; in vivo Model; insight; malignant breast neoplasm; mammary; migration; mouse model; neoplastic cell; novel diagnostics; premalignant; self-renewal; stem cell expansion; stem cells; stem-like cell; stemness; therapeutic target; three dimensional cell culture; tissue injury; tissue stem cells; tool; tumor; tumor initiation; tumorigenesis

PROJECT SUMMARY Alcohol consumption has been associated with increased breast cancer risk. Although alcohol-associated breast carcinogenesis has been extensively studied, the mechanisms of alcohol-induced tumor initiation, especially the primary cell targets in cancerous transformation, remains unclear. Recent advances indicate that deregulation of cancer stem cells (CSCs), a small group of tumor cells with self-renewal and differentiation potential, plays a central role in cancer initiation, development, and recurrence. The effects of alcohol consumption on breast cancer stem cells have been poorly understood. Nevertheless, studies showed that alcohol-induced liver oncogenesis involves CSC promotion. Alcohol-derived acetaldehyde (AA) induces chromosome rearrangement with functional consequences in hematopoietic stem cells, suggesting that tissue stem cells may be the primary target of alcohol/AA-associated genotoxicity. Supported by our preliminary studies showing that alcohol induces DNA damage, chromosome alterations and CSC expansion in breast cancer cell lines, this project aims to study whether and how alcohol consumption promotes cancer initiation through induction of CSCs from mammary stem cells (MaSCs). We hypothesize that alcohol promotes breast cancer development through AA-mediated gene mutations and genomic instability of MaSCs, which leads to the disruption of genome integration and cancerous transformation. The underlying mechanisms involve mutation of p53, impairment of DNA repair machinery and deregulation of stemness networks. In support of this study, we have developed the MMTV- erbB2/Aldh2-/- mouse model for mammary tumorigenesis and MaSC analysis. These unique tools will facilitate our studies on AA accumulation-associated toxicity in MaSCs in vivo. The hypothesis will be tested in three specific aims. 1) To determine whether alcohol and AA exposure promotes MaSC/CSC stemness and mammary tumor development in treated animals. 2) To examine alcohol/AA-induced genomic instability in mammary tumors and MaSCs/CSCs. 3) To understand the mechanisms of alcohol/AA-mediated genomic instability and MaSC/CSC deregulation focusing on p53 pathway and Wnt/Sox2/RANKL signaling network of mammary stemness. Results from this project will advance our understanding of alcohol-induced genomic injury and MaSC mutation that lead to malignant transformation in breast cancer initiation, and identify specific regulators that mediate these genetic and functional changes of the MaSCs and CSCs. These data will be of great significance for early diagnosis and prevention of alcohol-associated breast cancer.

项目摘要 饮酒与乳腺癌风险增加有关。虽然与酒精相关的乳房 癌变已经进行了广泛的研究，是酒精诱导的肿瘤起始的机制，尤其是 癌性转化中的主要细胞靶标仍然不清楚。最近的进步表明放松管制 癌症干细胞（CSC）是一小组具有自我更新和分化潜力的肿瘤细胞 中心作用在癌症的启动，发育和复发中。饮酒对乳房的影响 癌症干细胞的理解很少。然而，研究表明酒精引起的肝脏 肿瘤发生涉及CSC促进。酒精来源的乙醛（AA）诱导染色体重排 在造血干细胞中具有功能后果，这表明组织干细胞可能是主要的 酒精/与AA相关的遗传毒性的靶标。在我们的初步研究的支持下，酒精会诱导 DNA损伤，染色体改变和乳腺癌细胞系的CSC扩展，该项目旨在研究 是否以及如何通过乳腺CSC促进饮酒来促进癌症的启动 干细胞（MASC）。我们假设酒精通过AA介导的促进乳腺癌的发展 MASC的基因突变和基因组不稳定性，这导致基因组整合和 癌变转化。基本机制涉及p53突变，DNA修复的损害 干网络的机械和放松管制。为了支持这项研究，我们开发了MMTV- ERBB2/ALDH2 - / - 用于乳腺肿瘤发生和MA​​SC分析的小鼠模型。这些独特的工具将有助于 我们对AA积累与体内MASC的毒性相关的研究。该假设将在三个 具体目标。 1）确定酒精和AA暴露是否促进MASC/CSC茎和乳腺 治疗动物的肿瘤发展。 2）检查乳腺的酒精/AA诱导的基因组不稳定性 肿瘤和MASC/CSC。 3）了解酒精/AA介导的基因组不稳定性的机制和 MASC/CSC放松管制，重点是p53途径和Wnt/sox2/rankl信号网络 茎。该项目的结果将提高我们对酒精引起的基因组损伤和MASC的理解 导致乳腺癌开始中恶性转化的突变，并确定特定的调节剂 调解MASC和CSC的这些遗传和功能变化。这些数据将具有重要意义 为了早期诊断和预防酒精相关的乳腺癌。