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: 10705861
• 负责人: XIAOHE YANG
• 金额: $ 18.75万
• 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/10705861
• 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; Cell Separation; 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; Invaded; Karyotype determination procedure; Knock-out; Lesion; Liquid substance; Liver; Malignant - descriptor; Mammary Neoplasms; Mammary Tumorigenesis; Mammospheres; Mediating; Mediator; Methodology; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Mutate; Mutation; Neoplasm Metastasis; Pathogenesis; Pathway interactions; Play; Population; Premalignant Cell; Prevention; Process; Production; 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; 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.

项目总结