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

项目总结 饮酒与乳腺癌风险的增加有关。尽管与酒精相关的乳房 肿瘤的发生机制已经得到了广泛的研究，酒精诱发肿瘤的机制，特别是 癌症转化中的主要细胞靶点仍不清楚。最近的进展表明，放松管制 在肿瘤干细胞(CSCs)中，具有自我更新和分化潜能的一小群肿瘤细胞发挥着重要的作用 在癌症的发生、发展和复发中起核心作用。饮酒对乳房的影响 人们对癌症干细胞知之甚少。然而，研究表明，酒精诱导的肝脏 肿瘤发生涉及到CSC的促进作用。乙醇衍生乙醛(AA)诱发染色体重排 与造血干细胞的功能后果，表明组织干细胞可能是主要的 酒精/AA相关遗传毒性的靶标。我们的初步研究表明酒精会导致 本项目旨在研究乳腺癌细胞系的DNA损伤、染色体改变和CSC增殖 饮酒是否以及如何通过诱导乳腺肿瘤干细胞促进癌症的发生 干细胞(MASC)。我们假设酒精通过AA介导促进乳腺癌的发展 MASCS的基因突变和基因组不稳定性导致基因组整合和 癌变。其潜在机制包括P53基因突变、DNA修复功能受损 机械和放松对树干网络的管制。为支持这项研究，我们开发了MMTV- ERBB2/ALDH2-/-小鼠乳腺肿瘤发生模型及MASC分析这些独特的工具将促进 我们体内AA蓄积相关毒性的研究。这一假设将在三年内得到检验 明确的目标。1)确定酒精和AA暴露是否促进MASC/CSC干性和乳房 治疗动物体内的肿瘤发展。2)检测酒精/AA诱导的乳腺基因组不稳定性 肿瘤和MASCS/CSCs。3)了解酒精/AA介导的基因组不稳定性和 乳腺MASC/CSC对P53通路和Wnt/Sox2/RANKL信号网络的失控 茎干。该项目的结果将促进我们对酒精诱导的基因组损伤和MASC的理解 在乳腺癌启动过程中导致恶性转化的突变，并确定特定的调控因子 调节MASCs和CSCs的这些遗传和功能变化。这些数据将具有重要意义 用于酒精相关乳腺癌的早期诊断和预防。

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.