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

项目摘要 饮酒与乳腺癌风险增加有关。虽然酒精相关的乳腺癌 致癌作用已被广泛研究，酒精诱导的肿瘤发生机制，特别是 癌性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 癌症干细胞（CSCs）是一小群具有自我更新和分化潜能的肿瘤细胞， 在癌症的发生、发展和复发中起重要作用。饮酒对乳房的影响 对癌症干细胞的了解很少。然而，研究表明，酒精诱导的肝脏 肿瘤发生涉及CSC促进。酒精衍生的乙醛（AA）诱导染色体重排 在造血干细胞中具有功能性后果，这表明组织干细胞可能是主要的造血干细胞， 酒精/AA相关遗传毒性的靶点。我们的初步研究表明，酒精会诱导 本项目旨在研究乳腺癌细胞系中的DNA损伤、染色体改变和CSC扩增， 饮酒是否以及如何通过诱导乳腺癌干细胞促进癌症发生 干细胞（MaSCs）。我们假设酒精通过AA介导的 - MaSC的基因突变和基因组不稳定性，这导致基因组整合的破坏， 癌变其发生机制涉及p53基因突变、DNA修复功能障碍 机械和放松管制的主干网络。为了支持这项研究，我们开发了MMTV- 用于乳腺肿瘤发生和MaSC分析的erbB 2/Aldh 2-/-小鼠模型。这些独特的工具将有助于 我们在体内对MaSCs中AA积累相关毒性的研究。该假设将在三个测试 具体目标。1)为了确定酒精和AA暴露是否促进MaSC/CSC干性和乳腺癌， 治疗动物的肿瘤发展。2)检查酒精/AA诱导的乳腺癌细胞基因组不稳定性， 肿瘤和MaSC/CSC。3)了解酒精/AA介导的基因组不稳定性的机制， MaSC/CSC失调，聚焦于乳腺癌的p53通路和Wnt/Sox 2/RANKL信号网络 干性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 突变，导致乳腺癌的恶性转化开始，并确定具体的监管机构， 介导MaSC和CSC的这些遗传和功能变化。这些数据将具有重要意义 早期诊断和预防酒精相关性乳腺癌。

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.